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1. Assessment of DOAC in GEriatrics (Adage Study): Rivaroxaban/Apixaban Concentrations and Thrombin Generation Profiles in NVAF Very Elderly Patients

Author: Geoffrey Foulon-Pinto, Carmelo Lafuente-Lafuente, Georges Jourdi, Julien Le Guen, Fatoumata Tall, Etienne Puymirat, Maxime Delrue, Léa Rivière, Flora Ketz, Isabelle Gouin-Thibault, François Mullier, Pascale Gaussem, Eric Pautas, Thomas Lecompte, Emmanuel Curis, Virginie Siguret, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Laboratoire de biologie clinique, Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Catholique de Louvain = Catholic University of Louvain (UCL), Service d'hématologie A [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'angiologie et hémostase, Hôpitaux Universitaires de Genève (HUG), Geneva Planet Group, Université de Genève = University of Geneva (UNIGE), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), and Hôpital Lariboisière-Fernand-Widal [APHP]
Subjects: [SDV]Life Sciences [q-bio], Hematology
Abstract: Background Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions, and polypharmacy receive direct oral anticoagulants (DOACs), few studies specifically investigated both apixaban/rivaroxaban pharmacokinetics and pharmacodynamics in such patients. Aims To investigate: (1) DOAC concentration–time profiles; (2) thrombin generation (TG); and (3) clinical outcomes 6 months after inclusion in very elderly AF in-patients receiving rivaroxaban or apixaban. Methods Adage-NCT02464488 was an academic prospective exploratory multicenter study, enrolling AF in-patients aged ≥80 years, receiving DOAC for at least 4 days. Each patient had one to five blood samples at different time points over 20 days. DOAC concentrations were determined using chromogenic assays. TG was investigated using ST-Genesia (STG-ThromboScreen, STG-DrugScreen). Results We included 215 patients (women 71.1%, mean age: 87 ± 4 years), 104 rivaroxaban and 111 apixaban, and 79.5% receiving reduced-dose regimen. We observed important inter-individual variabilities (coefficient of variation) whatever the regimen, at C max [49–46%] and C min [75–61%] in 15 mg rivaroxaban and 2.5 mg apixaban patients, respectively. The dose regimen was associated with C max and C min plasma concentrations in apixaban (p = 0.0058 and p = 0.0222, respectively), but not in rivaroxaban samples (multivariate analysis). Moreover, substantial variability of thrombin peak height (STG-ThromboScreen) was noticed at a given plasma concentration for both xabans, suggesting an impact of the underlying coagulation status on TG in elderly in-patients. After 6-month follow-up, major bleeding/thromboembolic event/death rates were 6.7%/1.0%/17.3% in rivaroxaban and 5.4%/3.6%/18.9% in apixaban patients, respectively. Conclusion Our study provides original data in very elderly patients receiving DOAC in a real-life setting, showing great inter-individual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings.
Published: 2022

2. Pediatric cannabis intoxication in France and Belgium: A 3-year retrospective study

Author: Arbouche, Nadia, Gheddar, Laurie, Guyon, Joris, Matheux, Alice, Becam, Jenny, Boland, Lidvine, Bruno, Clément, Descoeur, Juliette, van den Eede, Nele, Lelong, Jeremy, Bellouard, Marie, Mernissi, Touria, Pelletier, Romain, Thiebot, Pauline, Willeman, Théo, Ameline, Alice, Fabresse, Nicolas, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut du Cancer de Montpellier (ICM), Hôpital de la Timone [CHU - APHM] (TIMONE), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Antwerp (UA), Service de pharmacocinétique [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Pontchaillou [Rennes], Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire de pharmacologie et de toxicologie neurocardiovasculaire (LPTNC), Université de Strasbourg (UNISTRA), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: Health, Toxicology and Mutagenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Toxicology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Cannabis is the most widely used drug in the world with a prevalence of 2.5%. France and Belgium are no exception. Moreover, pediatric cannabis intoxications are increasing due to the growing use of cannabis in the adult population. In this study, we seek to investigate whether there is a correlation between symptoms and biological data in order to facilitate the diagnosis of pediatric cannabis intoxication. Data were retrospectively collected from 11 French laboratories and 2 Belgian laboratories over 3-year period (2019–2021). This study involved 123 children aged 2 months to 4 years. There was a geographical gradient with an increase in intoxication cases from northern to southern regions. THC, 11-OH-THC and THC-COOH levels were respectively 24.4 ng/mL (range = 0.4–109 ng/mL; median = 17.3 ng/mL), 26.3 ng/mL (range = 0.6–263 ng/mL; median = 18 ng/mL) and 217 ng/mL (range = 0.6–921 ng/mL; median = 163 ng/mL). The most frequently observed symptom was drowsiness in 60.2% of cases. Coma (13.8%, n = 17), convulsions (4.1%, n = 5) and bradypnea (8.1%, n = 10) were the most severe symptoms. The increase of THC content in cannabis products could explain the increase in poisoning severity. However, according to the data collected, it does not seem that the clinical symptoms observed are correlated with plasma or blood THC concentrations. Indeed, cases of coma with Glasgow Coma Scale at 3 have been observed with plasma THC concentrations between 7 and 29 ng/mL.
Published: 2023

3. Pour accélérer la transition vers la durabilité et éviter l'érosion de sa puissance commerciale, l'Europe a besoin d'une politique forte et explicite en faveur de la biotechnologie industrielle

Author: O'Donohue, Michael, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Fractionnement des AgroRessources et Environnement (FARE), Université de Reims Champagne-Ardenne (URCA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT), Horizon 2020, INRAE, WUR, VTT, and CNR
Subjects: [SDV]Life Sciences [q-bio]
Abstract: To be the first climate-neutral continent and strengthen its global competitiveness, Europe needs to instigate and implement a robust, explicit policy that promotes the development of Industrial Biotechnology and Biomanufacturing. Biotechnology innovations can transform our economies, societies, and lives while tackling existential threats to Europe and the world, from climate change to pandemics.Already recognised by the European Commission as an advancedtechnology for industry, biotechnology contributed € 34.5 billion gross value added and supported 230,000 jobs in 2018 alone. In 2030, biotechnology is expected to contribute up to €100 billion to the EUeconomy and support one million jobs. Building on its long-lasting commitment to promoting biotechnology and biomanufacturing (partly as a reaction to increasingly strong China’s own priorities in the field), the US government has recently declared an executive order on advancing biotechnology andbiomanufacturing innovation supported by a $2 billion investment. In contrast with the US government,Europe lacks a strong and consistent pathway to Industrial Biotechnology and Biomanufacturing. Although Several Member States have launched national initiatives, there is an overall deficit of European coordination. This is regrettable because creating a strong synergy between national initiatives is the best way to draw benefits that will have an impact at the European scale. By playing a leading role in Industrial Biotechnology and Biomanufacturing and helping bring solutions that can change our lives, Europe can also close the innovation and technology gap with other major regions that are currently threatening its competitiveness, security, and long-term resilience.
Published: 2023

4. In mice and humans, brain microvascular contractility matures postnatally

Author: Leila Slaoui, Alice Gilbert, Armelle Rancillac, Barbara Delaunay-Piednoir, Audrey Chagnot, Quentin Gerard, Gaëlle Letort, Philippe Mailly, Noémie Robil, Antoinette Gelot, Mathilde Lefebvre, Maryline Favier, Karine Dias, Laurent Jourdren, Laetitia Federici, Sylvain Auvity, Salvatore Cisternino, Denis Vivien, Martine Cohen-Salmon, Anne-Cécile Boulay, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GenoSplice [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional d'Orléans (CHRO), Plateforme Histologie, Immunomarquage et Microdissection laser [Institut Cochin] (HistIM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Cohen-Salmon, Martine, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), GenomiqueENS (Genomique ENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Université Paris Descartes - Paris 5 (UPD5)
Subjects: [SDV] Life Sciences [q-bio], Postnatal development, Histology, General Neuroscience, [SDV]Life Sciences [q-bio], Vascular smooth muscle cell, microvessel contractility, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, Cerebral blood flow, Brain microvessels Postnatal development Vascular smooth muscle cell microvessel contractility Cerebral blood flow, Brain microvessels
Abstract: International audience; Although great efforts to characterize the embryonic phase of brain microvascular system development have been made, its postnatal maturation has barely been described. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific orpreferentially expressed transcripts. We found that endothelial cells (EC), vascular smooth muscle cells (VSMC) and fibroblasts (FB) follow specific molecular maturation programs over this time period. Focusing on VSMCs, we showed that arteriolar VSMC network expands and becomes contractile resulting in a greater cerebral blood flow (CBF), with heterogenous developmental trajectories within cortical regions. Samples of human brain cortex showed the same postnatal maturation process. Thus, the postnatal phase is a critical period during which arteriolar VSMC contractility required for vessel tone and brain perfusion is acquired and mature.
Published: 2022

5. Data manangement plan - IBISBA 1.0 (Version 3)

Author: O'Donohue, Michael, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Fractionnement des AgroRessources et Environnement (FARE), Université de Reims Champagne-Ardenne (URCA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), INRAE, and European Project: 730976,IBISBA 1.0
Subjects: [SDV]Life Sciences [q-bio]
Abstract: This deliverable addresses the request by the European Commission to establish a data managementplan. It is intended that this plan will evolve over the project duration. This present documentconstitutes the 2nd version of the data management plan, which provides overall guidelines and a basisfor further evolution before the end of the project. In particular, it covers the question of dataidentification, data description, standards and metadata, data sharing and data archiving. In the IBISBA1.0 project, a complete workpackage is dedicated to the development of e-tools for data andknowledge management and the project is operating a data management hub in cooperation with theFairdom initiative, a leading European association that promotes the principles of data FAIRization (i.e.making data Findable Accessible Interoperable Re-usable).
Published: 2022

6. Roadmap for the development of a sustainable IBISBA infrastructure

Author: O'Donohue, Michael, Tukiainen, Paulina, Debeche, Sonia, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Fractionnement des AgroRessources et Environnement (FARE), Université de Reims Champagne-Ardenne (URCA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT), Département Aliments, produits biosourcés et déchets - INRAE (TRANSFORM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biodiversité et Biotechnologie Fongiques (BBF), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), VTT Technical Research Centre of Finland (VTT), Commission européenne Horizon 2020, INRAE, and European Project: 730976,IBISBA 1.0
Subjects: [SDV]Life Sciences [q-bio]
Abstract: Deliverable 3.4 describing a roadmap to create IBISBA-ERIC. Addressing a gap in European industrial biotechnology, IBISBA’s mission is to provide world-class cutting-edge research infrastructure services enabling the development of industrial biotechnology as a technological cornerstone of the circular bioeconomy. In this regard, IBISBA aims to contribute to the delivery of Europe’s ambition to be the first climate neutral continent in 2050. To fulfil its mission, IBISBA is building an interoperable network involving some of Europe’s most significant, public-operated research infrastructures and the deployment of advanced digital networking tools. Belonging to IBISBA endows facilities with unprecedented collaborative capabilities that seamlessly link individual facility services and data assets within service workflows supporting whole R&D project life cycles. This means that IBISBA is uniquely geared to deliver translational research services, organizing the uptake and sharing of fundamental knowledge from different scientific disciplines to define new bioprocess concepts, build and test prototypes and perform pilot scale demonstrations. Since its origins in 2014, IBISBA has steadily grown in terms of numbers of partners involved, community maturity and organization. IBISBA’s progress has been significantly boosted by funding received in the framework of two European Horizon 2020 projects (IBISBA 1.0 and PREP-IBISBA, grant agreement numbers 730976 and 871118 respectively) and by enhanced recognition following its inclusion in 2018 the European Strategy Forum on Research Infrastructures’ roadmap. Presently, IBISBA is pursuing its progress towards a fully operational research infrastructure following a process that involves numerous preparative actions. Considering achievements so far, this report is a non-scientific action plan that outlines 25 vital actions that must be successfully accomplished to deliver IBISBA’s ambition, launching a legal entity before 2025 to achieve this. Some of these actions have already been reached, while other actions are ongoing or planned.
Published: 2022

7. N–H⋯X interactions stabilize intra-residue C5 hydrogen bonded conformations in heterocyclic $\alpha$-amino acid derivatives

Author: Viola C. D'mello, Sylvie Robin, Venkateswara Rao Mundlapati, Michel Mons, Jean-Pierre Baltaze, Valérie Brenner, Zeynab Imani, David J. Aitken, Eric Gloaguen, LUmière et MOlécules (LUMO), Institut Rayonnement Matière de Saclay (IRAMIS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire Interactions, Dynamiques et Lasers (ex SPAM) (LIDyl), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Grant 2020-A0070807540 awarded by GENCI (Grand Equipement National de Calcul Intensif), The CCRT High Performance Computing (HPC) facility at CEA under the Grant CCRT2020-p606bren, ANR-17-CE29-0008,TUNIFOLD-S,Le soufre pour contrôler la flexibilité de briques moléculaires(2017), and ANR-10-LABX-0039,PALM,Physics: Atoms, Light, Matter(2010)
Subjects: chemistry.chemical_classification, Hydrogen, 010405 organic chemistry, Chemistry, Hydrogen bond, Heteroatom, chemistry.chemical_element, General Chemistry, 010402 general chemistry, Ring (chemistry), 01 natural sciences, Quantum chemistry, Acceptor, 0104 chemical sciences, 3. Good health, Amino acid, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Residue (chemistry), Crystallography
Abstract: Nature makes extensive and elaborate use of hydrogen bonding to assemble and stabilize biomolecular structures. The shapes of peptides and proteins rely significantly on N–H⋯O Created by potrace 1.16, written by Peter Selinger 2001-2019 C interactions, which are the linchpins of turns, sheets and helices. The C5 H-bond, in which a single residue provides both donor and acceptor, is generally considered too weak to force the backbone to adopt extended structures. Exploiting the synergy between gas phase (experimental and quantum chemistry) and solution spectroscopies to decipher IR spectroscopic data, this work demonstrates that the extended C5-based conformation in 4-membered ring heterocyclic α-amino acid derivatives is significantly stabilized by the formation of an N–H⋯X H-bond. In this synergic system the strength of the C5 interaction remains constant while the N–H⋯X H-bond strength, and thereby the support provided by it, varies with the heteroatom., In 4-membered ring heterocyclic α-amino acid derivatives, extended conformations based on intraresidue C5 H-bonds can be stabilized by N–H⋯X H-bonds, making the combined C5–C6γ structures prominent in both gas phase and in weakly polar solutions.
Published: 2021

8. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Author: Magdalena Harakalova, Benjamin Meder, Philippe Charron, Manuel Gómez-Bueno, Jorg J. A. Calis, François Cambien, David-Alexandre Trégouët, Maurizia Grasso, Steven McGinn, Uwe Völker, Thomas Meitinger, Stefan Weiss, L. Duboscq-Bidot, Richard Dorent, Vera Regitz-Zagrosek, Folkert W. Asselbergs, Hélène Blanché, Olivier Dubourg, Patrick Lacolley, Pierre Boutouyrie, Delphine Bacq-Daian, Vincent Fontaine, Volker Ruppert, Marine Germain, K Lehnert, Jean-Noël Trochu, Stuart A. Cook, Angélique Curjol, Brendan J. Keating, Ibticem Raji, Anne Boland, J. Erdmann, Michael Morley, Jean-François Aupetit, Paloma Remior, Luigi Tavazzi, Gérard Roizès, Michal Mokry, Konstantin Strauch, Richard Isnard, Jean-Philippe Empana, Robert Olaso, Kenneth B. Marguiles, Zofia T. Bilińska, Stephan B. Felix, Marcus Dörr, Thomas P. Cappola, Stefan Blankenberg, Jan Haas, Céline Besse, Jean-François Deleuze, Christine E. Seidman, Christian Hengstenberg, Jessica van Setten, Hakon Hakonarson, Sanjay K Prasad, Daiane Hemerich, Pascal de Groote, Thomas Wichter, Alain van Mil, Michel Komajda, Renee Maas, Carole Proust, Declan P. O'Regan, Xavier Jouven, Ganapathi Varma Saripella, Georgios Kararigas, Eloisa Arbustini, Jin Li, Klaus Stark, Laurent Fauchier, Flavie Ader, Melanie Waldenberger, Martina Müller-Nurasyid, Eric Villard, Sophie Garnier, Cardiology, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique-Hôpitaux de Paris, Fondation Leducq, Société Française de Cardiologie, Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München, Université de Bordeaux, Medical Research Council, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University Medical Center [Utrecht], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Pennsylvania, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), National Heart Centre Singapore (NHCS), Children’s Hospital of Philadelphia (CHOP ), University of Regensburg, Royal Brompton Hospital, Imperial College London, Istituti Clinici Scientifici Maugeri [Pavia] (IRCCS Pavia - ICS Maugeri), Helmholtz Zentrum München = German Research Center for Environmental Health, Ludwig-Maximilians-Universität München (LMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University Medical Center of the Johannes Gutenberg-University Mainz, Perelman School of Medicine, Harvard Medical School [Boston] (HMS), University of Iceland [Reykjavik], Heidelberg University, Stanford University Medical School, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universität zu Lübeck = University of Lübeck [Lübeck], Universitätklinikum Gießen und Marburg GmbH, Maria Cecilia Hospital [Cotignola], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier Saint Joseph - Saint Luc [Lyon], National Institute of Cardiology [Varsovie, Pologne], University of Medicine Greifswald, Centre de Référence Maladies Cardiaques Héréditaires, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Swedish University of Agricultural Sciences (SLU), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Groupe Hospitalier Paris Saint Joseph, Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), and University College of London [London] (UCL)
Subjects: Cardiac & Cardiovascular Systems, Cardiomyopathy, Dilated/genetics, [SDV]Life Sciences [q-bio], Signal Transducing/genetics, Dilated cardiomyopathy, Genome-wide association study, Adaptor Proteins, Signal Transducing/genetics, 030204 cardiovascular system & hematology, TAURINE, 0302 clinical medicine, GWAS, Medicine, POSITION STATEMENT, 1102 Cardiorespiratory Medicine and Haematology, Genetics, 0303 health sciences, education.field_of_study, Genetic Predisposition to Disease/genetics, Adaptor Proteins, 4C-sequencing, Polymorphism, Single Nucleotide/genetics, Genetic risk score, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Single Nucleotide/genetics, Cardiomyopathy, Dilated, Cardiomyopathy, Population, Locus (genetics), Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Chromosomes, 03 medical and health sciences, Systolic/genetics, Heart Failure, Systolic/genetics, SNP, Animals, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, Imputation, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Heart Failure, Science & Technology, business.industry, WORKING GROUP, 1103 Clinical Sciences, medicine.disease, Genetic architecture, Cardiovascular System & Hematology, Dilated/genetics, Cardiovascular System & Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Apoptosis Regulatory Proteins, Heart Failure, Systolic, Genome-Wide Association Study
Abstract: Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
Published: 2021

9. Dabigatran Level Before Reversal Can Predict Hemostatic Effectiveness of Idarucizumab in a Real-World Setting

Author: Nicolas Gendron, Richard Chocron, Paul Billoir, Julien Brunier, Laurence Camoin-Jau, Marie Tuffigo, Dorothée Faille, Dorian Teissandier, Juliette Gay, Emmanuelle de Raucourt, Ludovic Suner, Corentin Bonnet, Anne-Céline Martin, Dominique Lasne, Chayma Ladhari, Aurélien Lebreton, Laurent Bertoletti, Nadine Ajzenberg, Pascale Gaussem, Pierre-Emmanuel Morange, Véronique Le Cam Duchez, Alain Viallon, Pierre-Marie Roy, Agnès Lillo-le Louët, David M. Smadja, Lucas, Nelly, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Rhumatologie [CHU Pellegrin], Groupe hospitalier Pellegrin, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine et d'épidémiologie appliquée [AP-HP Hôpital Bichat-Claude Bernard] (IMEA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Sud Saint Pierre [Ile de la Réunion], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de compétence de la Sclérose Latérale Amyotrophique [CHU Clermont-Ferrand] (SLA), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140)
Subjects: rebound, 030204 cardiovascular system & hematology, Dabigatran, 03 medical and health sciences, idarucizumab, 0302 clinical medicine, hemostatic effectiveness, Antithrombotic, medicine, dabigatran, 030212 general & internal medicine, perioperative, Original Research, lcsh:R5-920, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Incidence (epidemiology), Retrospective cohort study, Idarucizumab, General Medicine, Perioperative, bleeding, Anesthesia, Hemostasis, Medicine, reversal, lcsh:Medicine (General), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, Cohort study
Abstract: Background: Idarucizumab has been included in guidelines for the management of bleeding or surgical procedure in dabigatran-treated patients without need for biological monitoring. The aim of the study was to assess the prognostic value of dabigatran plasma level before reversal to test the hemostatic efficacy of idarucizumab. The secondary objectives were (i) to analyze plasma dabigatran level according to the risk of rebound and (ii) to evaluate the incidence of post-reversal non-favorable clinical outcomes (including thromboembolism, bleeding, antithrombotic, and death) and antithrombotic resumption.Methods and Results: This was an observational multicentric cohort study, which included all French patients who required idarucizumab for dabigatran reversal. Between May 2016 and April 2019, 87 patients from 21 French centers were enrolled. Patients received idarucizumab for overt bleeding (n = 61), urgent procedures (n = 24), or overdose without bleeding (n = 2). Among patients with major bleeding (n = 57), treatment with idarucizumab was considered effective in 44 (77.2%) of them. Patients who did not achieve effective hemostasis after reversal had a significantly higher mean level of plasma dabigatran at baseline (524.5 ± 386 vs. 252.8 ng/mL ± 235, p = 0.033). Furthermore, patients who did not achieve effective hemostasis after reversal had less favorable outcomes during follow-up (46.2 vs. 81.8%, p = 0.027). ROC curve identified a cutoff of 264 ng/mL for dabigatran level at admission to be predictive of ineffective hemostasis. No plasma dabigatran rebound was observed after reversal in patients with dabigatran plasma level < 264 ng/mL at baseline.Conclusion: This retrospective study shows that dabigatran level before reversal could predict hemostatic effectiveness and dabigatran plasma rebound after idarucizumab injection.
Published: 2020

10. Industrial biotechnology is an advanced technology at the heart of the bioeconomy and the circular economy: its development needs efforts from the public sector

Author: O'Donohue, Michael, Di Fenza, Mauro, Debeche, Sonia, Penttilä, Merja, Martins Dos Santos, Vitor, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Fractionnement des AgroRessources et Environnement (FARE), Université de Reims Champagne-Ardenne (URCA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT), Biodiversité et Biotechnologie Fongiques (BBF), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Wageningen University and Research [Wageningen] (WUR), Consiglio Nazionale delle Ricerche [Potenza] (CNR), European Commission Horizon 2020, and INRAE
Subjects: MESH: Biotechnology, Chemical Process Engineering, Research infrastructure, [SPI]Engineering Sciences [physics], [SDV]Life Sciences [q-bio], Biotechnology
Abstract: • Breakthroughs in engineering biology, such as synthetic biology, are impulsing new developments in industrial biotechnology andprovide low carbon solutions for societal challenges.• Industrial Biotechnology is relevant to the bioeconomy and the circular economy because it provides solutions to valorise biobasedresources, including organic residues and waste streams.• The combination of biobased and digital technologies is generating new opportunities to develop advanced manufacturingprocesses, products and services.• The EU must increase its investments in biotechnology to acquire greater manufacturing autonomy taking back control over strategicvalue chain.• Tomorrow's industrial biotechnology will contribute significantly to efforts to achieve the aims of the Green Deal and those of UNSustainable Development Goals
Published: 2020

11. Intravenous infusion for the controlled exposure to the dual ABCB1 and ABCG2 inhibitor elacridar in nonhuman primates

Author: Sébastien Goutal, Xavier Declèves, Karine Andrieux, Fabien Caillé, Oliver Langer, Christine Coulon, Sylvain Auvity, Philippe Gervais, Salvatore Cisternino, Nicolas Tournier, Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medizinische Universität Wien = Medical University of Vienna, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: PHARMACOKINETICS, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Abcg2, BIOAVAILABILITY, Continuous infusion, Pharmaceutical Science, Pharmacology, Blood–brain barrier, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, medicine, P-glycoprotein, biology, BLOOD-BRAIN-BARRIER, Chemistry, Venous Plasma, Transporter, TRANSPORTERS, 3. Good health, Bioavailability, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, MONKEYS, 030217 neurology & neurosurgery
Abstract: International audience; Elacridar (GF120918) is a highly potent inhibitor of both P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), the main efflux transporters expressed at the blood-brain barrier (BBB). Elacridar shows very low aqueous solubility, which complicates its formulation for i.v. administration. An intravenous infusion protocol would be preferred to achieve high and controlled plasma concentrations of elacridar in large animals, including nonhuman primates. Formulation of elacridar for i.v. infusion was achieved using a co-solvent strategy, resulting in an aqueous dispersion with a final concentration of 5 g L-1 elacridar with tetrahydrofuran (5% w/v) in aqueous D-glucose solution (2.5%, w/v). Particle size (mean = 2.8 +/- 0.9 mu m) remained stable for 150 min. The preparation was i.v. administered as a continuous infusion (12 mg kg(-1) h(-1) for 90 min) to three baboons. Arterial and venous plasma pharmacokinetics (PK) of elacridar were monitored using a newly developed and validated HPLCUV method. Elacridar concentration increased rapidly to reach a plateau at 9.5 mu g mL(-1) within 20 min after the start of infusion. Elacridar PK in venous plasma did not differ firm arterial plasma facing the BBB, indicating the absence of an arteriovenous concentration gradient. Intravenous infusion of elacridar allows for controlled exposure of the BBB and offers a useful tool to assess the impact of ABCB1/ABCG2 on drug disposition to the brain in nonhuman primates, a relevant animal model for the study of transporter function at the BBB.
Published: 2018

12. Imaging Probes and Modalities for the Study of Solute Carrier O (SLCO)-Transport Function In Vivo

Author: Xavier Declèves, Solène Marie, Salvatore Cisternino, Nicolas Tournier, Irène Buvat, Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Faculté de Pharmacie [Châtenay-Malabry], Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine)-Université Paris-Saclay, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), ANR-16-CE17-0011,ISOTOPK,Imagerie fonctionnelle des transporteurs SLCO (Solute Carrier O) chez l'Homme : implication dans la variabilité d’élimination et de distribution tissulaire des médicaments(2016), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-16-CE17-0011,ISOTOPK,Imagerie fonctionnelle des transporteurs SLCO (Solute Carrier O) chez l'Homme : implication dans la variabilité d'élimination et de distribution tissulaire des médicaments(2016), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay-Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Decleves, Xavier
Subjects: Pathology, medicine.medical_specialty, Solute transporters, [SDV]Life Sciences [q-bio], Organic Anion Transporters, Hepatic transport, Pharmaceutical Science, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, 030226 pharmacology & pharmacy, Substrate Specificity, solute transporters, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, Organic anion-transporting polypeptide transporters, In vivo, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Animals, Humans, Modalities, medicine.diagnostic_test, Drug disposition, Chemistry, Biological Transport, Magnetic resonance imaging, Imaging methods, 3. Good health, Solute carrier family, [SDV] Life Sciences [q-bio], Pharmaceutical Preparations, Positron emission tomography, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Indicators and Reagents, Emission computed tomography, Function (biology)
Abstract: International audience; Transporters of the Solute Carrier O (SLCO) family, former organic anion-transportingpolypeptides (OATP), are now recognized as key players in pharmacokinetics. Imagingis increasingly regarded as a relevant method to elucidate and decipher the intrinsicrole of SLCO in controlling drug disposition in plasma and tissues. Current research inthis representative field of translational research is based on different imagingmodalities including nuclear imaging, such as Single Photon Emission ComputedTomography (SPECT) or Positron Emission Tomography (PET), as well as MagneticResonance Imaging (MRI). Imaging modalities can be compared in terms of sensitivity,quantitative properties, spatial resolution, variety of ligands and radiation exposure. Allof these approaches rely on the use of SLCO-substrates that are detected usingcorresponding modalities. The present review aims at reporting and comparing theimaging probes that have been proposed to study SLCO-transport function, in termsof $in\ vitro$ specificity, $in\ vivo$ behavior and clinical validation.
Published: 2017

13. Pitfalls and feedback when constructing topological pressure-temperature phase diagrams

Author: Siro Toscani, René Céolin, J. Ll. Tamarit, Ivo B. Rietveld, Maria Barrio, Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Universitat Politècnica de Catalunya [Barcelona] (UPC), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Spanish Ministry of Science and Innovation [FIS2014-54734-P], Generalitat de Catalunya [2014 SGR-581], Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universitat Politècnica de Catalunya. Departament de Física, Universitat Politècnica de Catalunya. GCM - Grup de Caracterització de Materials, Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Universitat Politècnica de Catalunya [Barcelona] ( UPC ), Institut des Sciences Chimiques de Rennes ( ISCR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Ecole Nationale Supérieure de Chimie de Rennes-Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)
Subjects: Polymorphism (Crystallography), Diagrames de fase, General Physics and Astronomy, 02 engineering and technology, Type (model theory), 030226 pharmacology & pharmacy, Stability (probability), 03 medical and health sciences, 0302 clinical medicine, Consistency (statistics), Simple (abstract algebra), Trimorphism, Phase diagrams, General Materials Science, Statistical physics, Physical and Theoretical Chemistry, Phase diagram, Physics, Crystallography, Física [Àrees temàtiques de la UPC], Hierarchy (mathematics), 021001 nanoscience & nanotechnology, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Topological pressure, [ CHIM.THEO ] Chemical Sciences/Theoretical and/or physical chemistry, 0210 nano-technology
Abstract: International audience; The stability hierarchy between different phases of a chemical compound can be accurately reproduced in a topological phase diagram. This type of phase diagrams may appear to be the result of simple extrapolations, however, experimental complications quickly increase in the case of crystalline trimorphism (and higher order polymorphism). To ensure the accurate positioning of stable phase domains, a topological phase diagram needs to be consistent. This paper gives an example of how thermodynamic feedback can be used in the topological construction of phase diagrams to ensure overall consistency in a phase diagram based on the case of piracetam crystalline trimorphism.
Published: 2017

14. Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

Author: Audrey Carlo, Isabelle Gouin-Thibault, Patrick Mismetti, Xavier Delavenne, Pascale Gaussem, Thomas Lecompte, Marie-Anne Loriot, Joe-Elie Salem, Emmanuel Curis, Christian Funck-Brentano, Anne Blanchard, Virginie Siguret, Johan Abdoul, Michel Azizi, Université Paris-Est Marne-la-Vallée (UPEM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Diagnostica Stago, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Paris Est, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Paris, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Groupe de recherche sur la thrombose, pharmacologie des antithrombotiques et situations à risque (GRT), Université Jean Monnet - Saint-Étienne (UJM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'investigation clinique Paris Est (CIC Paris-Est), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Jonchère, Laurent, Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Adult, Male, medicine.drug_mechanism_of_action, Adolescent, Genotype, [SDV]Life Sciences [q-bio], Population, Factor Xa Inhibitor, 030204 cardiovascular system & hematology, Pharmacology, Thrombomodulin, Models, Biological, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pharmacokinetics, Rivaroxaban, medicine, Humans, education, Blood Coagulation, ComputingMilieux_MISCELLANEOUS, pharmacodynamic model, education.field_of_study, Biological Variation, Individual, Cross-Over Studies, Chemistry, Thrombin, thrombomodulin, Hematology, Active protein, Middle Aged, Healthy Volunteers, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Enzyme Activation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, thrombin generation, Pharmacodynamics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Drug Monitoring, Blood sampling, medicine.drug, ATP Binding Cassette Transporter 1, Factor Xa Inhibitors, Protein C
Abstract: Background Rivaroxaban is a direct factor Xa inhibitor with substantial inter-individual pharmacokinetic (PK) variability. Pharmacodynamic (PD) variability, especially assessed with thrombin generation (TG), has been less documented. Objectives (i) To assess TG parameter time profiles in healthy volunteers, with TG being studied under different conditions and (ii) to model the relationship between rivaroxaban concentrations and TG parameters and subsequently estimate interindividual variability. Methods Sixty healthy male volunteers (DRIVING-NCT01627665) received a single 40-mg rivaroxaban dose. Blood sampling was performed at baseline and 10 predefined time points over 24 h. The TG was investigated with the fully automated ST-Genesia system (Stago), using two tissue-factor (TF) concentrations, in the absence (-), or presence (+) of thrombomodulin (TM) for the lowest one. The PD models were built to characterize the relationships between plasma rivaroxaban concentrations and endogenous thrombin potential (ETP) or peak height induced by the lowest TF concentration. Results Thrombin generation parameter time profiles with the lowest TF concentration showed a good sensitivity to rivaroxaban, especially +TM (active protein C negative feedback). The relationship between rivaroxaban concentrations and TG parameters was modeled with a sigmoidal relation. Mean rivaroxaban concentrations halving the baseline value of ETP and peak height (-TM) (C50 ) were of 284 and 33.2 ng/mL, respectively: +TM, C50 declined to 19.4 and 13.8 ng/mL, reflecting a powerful inhibitory effect. The estimated C50 population coefficients of variation were of 12.2% (-TM) and 31.3% (+TM) with the peak height models, 34.8% (+TM) with the ETP model. Conclusions This low-rivaroxaban to moderate-rivaroxaban PD variability in healthy volunteers contrasts with the substantial PK variability and deserves to be studied in different patient settings.
Published: 2019

15. 2nd PSL Chemical Biology Symposium (2019): At the Crossroads of Chemistry and Biology

Author: Marco Lucchino, Alain Wagner, Philippe Belmont, Christine Gaillet, Antoine Versini, Muriel Delepierre, Bhanudas Dasari, Tatiana Cañeque, Philippe Karoyan, Christophe M. Thomas, Harikrishna Bavireddi, Sylvain Debieu, Arnaud Gautier, Sébastien Britton, Anne Billet, David Monchaud, Frédéric Taran, Géraldine Masson, Ludger Johannes, Raphaël Rodriguez, Jean-Claude Florent, Frederic Schmidt, Janine Cossy, Anne Houdusse, Ludovic Colombeau, Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Réactions et Génie des Procédés (LRGP), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS), Service de Chimie Bio-Organique et de Marquage (SCBM), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie et des Matériaux Paris-Est (ICMPE), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Curie, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris-Sciences-et-Lettres (https://www.psl.eu/), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Curie [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Curie, PSL Research University, CNRS UMR3664, Paris, France., Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Paris, biocatalysis, natural products, [SDV]Life Sciences [q-bio], Chemical biology, antibody-drug conjugates, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biology, 010402 general chemistry, 01 natural sciences, Biochemistry, Human health, Humans, [CHIM]Chemical Sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, bionanotechnology, antibody-drug conjugates, biocatalysis, bionanotechnology, natural products, targeted therapeutics, Molecular Biology, targeted therapeutics, ComputingMilieux_MISCELLANEOUS, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, 0104 chemical sciences, Molecular Medicine, Engineering ethics, [CHIM.OTHE]Chemical Sciences/Other
Abstract: Chemical Biology is the science of designing chemical tools to dissect and manipulate biology at different scales. It provides the fertile ground from which to address important problems of our society, such as human health and environment.
Published: 2019

16. Minimal nanodisc without exogenous lipids for stabilizing membrane proteins in detergent-free buffer

Author: Sébastien Mongrand, Cyril Garnier, Marion Decossas, Olivier Lambert, Sophie Lecomte, Jean Christophe Taveau, Gilles Phan, Guy Schoehn, Marie Glavier, Isabelle Broutin, Dimitri Salvador, Laetitia Daury, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Laboratoire de biogenèse membranaire (LBM), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Platefome de Microscopie électronique IBS/ISBG, ANR-10-INBS-05-01/10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049/10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), UMR 5248 Chimie et Biologie des Membranes et des Nano-objets, Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Scaffold protein, Biophysics, Buffers, 010402 general chemistry, 01 natural sciences, Biochemistry, Micelle, Buffer (optical fiber), 03 medical and health sciences, Membrane Lipids, parasitic diseases, Nanodisc, 030304 developmental biology, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Cryoelectron Microscopy, Transporter, Cell Biology, [CHIM.MATE]Chemical Sciences/Material chemistry, Lipids, Transmembrane protein, 0104 chemical sciences, Nanostructures, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Membrane, Membrane protein, CryoEM, Bacterial Outer Membrane Proteins
Abstract: International audience; Membrane protein stabilization after detergent solubilization presents drawbacks for structural and biophysical studies, in particular that of a reduced stability in detergent micelles. Therefore, alternative methods are required for efficient stabilization. Lipid nanodisc made with the membrane scaffold protein MSP is a valuable system but requires a fine optimization of the lipid to protein ratio. We present here the use of the scaffold protein MSP without added lipids as a minimal system to stabilize membrane proteins. We show that this method is applicable to α-helical and β-strands transmembrane proteins. This method allowed cryo-electron microscopy structural study of the bacterial transporter MexB. A protein quantification indicates that MexB is stabilized by two MSP proteins. This simplified and efficient method proposes a new advance in harnessing the MSP potential to stabilize membrane proteins.
Published: 2019

17. Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1) study protocol of a phase II trial

Author: Estelle Boivin, Vincent Jullien, Elie Saliba, Catherine Mouchel, Géraldine Favrais, Moreno Ursino, Sarah Zohar, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), French Ministry of Health, Science et Technologie du Lait et de l'Oeuf (STLO), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Imagerie et Cerveau (iBrain - Inserm U1253 - UNIV Tours), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Jonchère, Laurent
Subjects: Pediatrics, medicine.medical_specialty, levetiracetam, seizure, Encephalopathy, Context (language use), phase li trial, Loading dose, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Clinical Trials, Phase II as Topic, Pharmacokinetics, Seizures, newborn, 030225 pediatrics, Intensive care, medicine, Protocol, Humans, Multicenter Studies as Topic, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Dose-Response Relationship, Drug, business.industry, Maintenance dose, Infant, Newborn, Paediatrics, General Medicine, medicine.disease, hypoxic-ischaemic encephalopathy, 3. Good health, Treatment Outcome, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Hypoxia-Ischemia, Brain, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Phenobarbital, Anticonvulsants, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Levetiracetam, France, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: IntroductionTherapeutic schedules for treating neonatal seizures remain elusive. First-line treatment with phenobarbital is widely supported but without strong scientific evidence. Levetiracetam (LEV) is an emerging and promising antiepileptic drug (AED). The aim of this phase II trial is to determine the benefits of LEV by applying a strict methodology and to estimate the optimal dose of LEV as a first-line AED to treat seizures in newborns suffering from hypoxic-ischaemic encephalopathy.Methods and analysisLEVNEONAT-1 is an open and sequential LEV dose-finding study. The optimal dose is that which is estimated to be associated with a toxicity not exceeding 10% and an efficacy higher than 60%. Efficacy is defined by a seizure burden reduction of 80% after the loading dose. Four increasing dose regimens will be assessed including one loading dose of 30, 40, 50 or 60 mg/kg followed by eight maintenance doses (ie, a quarter of the loading dose) injected every 8 hours. A two-patient cohort will be necessary at each dose level to consider an upper dose level assignment. The maximal sample size expected is 50 participants with a minimum of 24 patients or fewer in the case of a high rate of toxicity. Patients will be recruited in five neonatal intensive care units beginning in October 2017 and continuing for 2 years. In parallel, the LEV pharmacokinetics will be measured five times (ie, 30 min; 4 and 7 hours after the loading dose; 1–3 hours and 12–18 hours after the last maintenance dose).Ethics and disseminationEthics approval has been obtained from the regional ethical committee (2016-R25) and the French Drug Safety Agency (160652A-31). The results will be published in a peer-reviewed journal. The results will also be presented at medical meetings.Trial registration numberNCT02229123; Pre-results.
Published: 2019

18. Strategies of neutralization of the direct oral anticoagulants effect: review of the literature

Author: Isabelle Gouin-Thibault, Bernard Le Bonniec, G Jourdi, Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Cochin [AP-HP]
Subjects: 030213 general clinical medicine, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Antidotes, Administration, Oral, Hemorrhage, Pharmacology, Neutralization, Antithrombins, Dabigatran, Food and drug administration, 03 medical and health sciences, 0302 clinical medicine, Rivaroxaban, xabans, medicine, pro-hemostatic agent, Humans, coagulation, Antidote, business.industry, Anticoagulants, Idarucizumab, Hematology, General Medicine, Recombinant Proteins, 3. Good health, Coagulation, Factor Xa, business, antidote, Ex vivo, medicine.drug, Discovery and development of direct thrombin inhibitors, Factor Xa Inhibitors
Abstract: International audience; Many neutralizing agents of anticoagulant effect of factor Xa or thrombin inhibitors (xabans and dabigatran, respectively) have been developed since the commercialization of direct oral anticoagulants (DOAC) in 2008. Idarucizumab is a specific antidote of dabigatran commercialised since 2016. An antidote of xabans, andexanet-α, was very recently approved by the Food and Drug Administration (FDA). Other antidotes of DOAC are under pre-clinical or clinical development; the most advanced being the aripazine in addition to γ-thrombine S195A and GDFXa-αM complex. Prothrombin complex concentrates activated or not, are part of the pro-hemostatic agents suggested for DOAC handling in case of haemorrhage or preceeding urgent surgery or invasive procedures. Other pro-hemostatic agents (FXa, FX (a)-C, FVa) are in pre-clinical stage. The efficacy of these different agents in DOAC reversal and mortality reduction is still controversal in the light of the sparse results of in vitro, ex vivo, pre-clinical and clinical studies.
Published: 2018

19. The lipidome associated with the γ-secretase complex is required for its integrity and activity

Author: Andrej Shevchenko, Mohamed Chami, Sophie Ayciriex, Hermeto Gerber, Henning Stahlberg, Guillermo M. Garcia Osuna, Patrick C. Fraering, Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon, Laboratoire d'océanographie de Villefranche ( LOV ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Max Planck Institute of Molecular Cell Biology and Genetics ( MPI-CBG ), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Laboratoire d'océanographie de Villefranche (LOV), Observatoire océanologique de Villefranche-sur-mer (OOVM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire océanologique de Villefranche-sur-mer (OOVM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.medical_treatment, Biochemistry, Substrate Specificity, lipid microenvironment, Amyloid beta-Protein Precursor, chemistry.chemical_compound, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], lipid species, APH-1, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, gamma-secretase, intramembrane-cleaving protease, mass spectrometry, chemistry.chemical_classification, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Lipidome, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 3. Good health, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Intramembrane protease, Proteolipids, Biology, 03 medical and health sciences, proteoliposomes, Alzheimer Disease, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Phosphatidylcholine, medicine, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, Gamma secretase, quantitative shotgun lipidomics, Protease, Cholesterol, Cell Biology, Lipid Metabolism, 030104 developmental biology, Enzyme, chemistry, biology.protein, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, Amyloid Precursor Protein Secretases, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: gamma-Secretase is a multi-subunit membrane protease complex that catalyses the final intramembrane cleavage of the beta-amyloid precursor protein (APP) during the neuronal production of amyloid-beta peptides (A beta), which are implicated as the causative agents of Alzheimer's disease (AD). In the present study, we report the reconstitution of a highly purified, active gamma-secretase complex into proteoliposomes without exogenous lipids and provide the first direct evidence for the existence of a microenvironment of 53 molecular species from 11 major lipid classes specifically associated with the gamma-secretase complex, including phosphatidylcholine and cholesterol. Importantly, we demonstrate that the pharmacological modulation of certain phospholipids abolishes both the integrity and the enzymatic activity of the intramembrane protease. Together, our findings highlight the importance of a specific lipid microenvironment for the structure and function of gamma-secretase.
Published: 2016

20. High-level artemisinin-resistance with quinine co-resistance emerges in P. falciparum malaria under in vivo artesunate pressure

Author: Laurent A. Decosterd, Piero Olliaro, Pierre Druilhe, Eric Prieur, Ludovic Arnold, Jean-Louis Pérignon, Rachida Tahar, Patrick J. Gleeson, Rajeev K. Tyagi, Vac4all initiative, Parasitologie Biomédicale, Institut Pasteur [Paris] (IP), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Institut de Recherche pour le Développement (IRD), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre for Tropical Medicine and Global Health, University of Oxford, This work was funded by the Vac4All Initiative. The initial mouse model employed was developed by the Bio-Medical Parasitology Unit at Institut Pasteur. Vac4all thereafter covered the expenses of personnel, reagents, animals, molecular studies, rent, and sundries required to gather the results presented., Institut Pasteur [Paris], Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Bodescot, Myriam
Subjects: Male, 0301 basic medicine, Resistance, Drug Resistance, lcsh:Medicine, Artesunate, Mice, SCID, Drug resistance, Pharmacology, Mice, chemistry.chemical_compound, 0302 clinical medicine, Mice, Inbred NOD, NSG mice, Malaria, Falciparum, Artemisinin, Quinine, biology, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Artemisinins, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Female, Research Article, medicine.drug, Combination therapy, 030106 microbiology, 030231 tropical medicine, P. falciparum, Antimalarials, 03 medical and health sciences, parasitic diseases, medicine, Animals, Humans, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, business.industry, lcsh:R, Plasmodium falciparum, medicine.disease, biology.organism_classification, Malaria, Multiple drug resistance, chemistry, business
Abstract: Background Humanity has become largely dependent on artemisinin derivatives for both the treatment and control of malaria, with few alternatives available. A Plasmodium falciparum phenotype with delayed parasite clearance during artemisinin-based combination therapy has established in Southeast Asia, and is emerging elsewhere. Therefore, we must know how fast, and by how much, artemisinin-resistance can strengthen. Methods P. falciparum was subjected to discontinuous in vivo artemisinin drug pressure by capitalizing on a novel model that allows for long-lasting, high-parasite loads. Intravenous artesunate was administered, using either single flash-doses or a 2-day regimen, to P. falciparum-infected humanized NOD/SCID IL-2Rγ−/−immunocompromised mice, with progressive dose increments as parasites recovered. The parasite’s response to artemisinins and other available anti-malarial compounds was characterized in vivo and in vitro. Results Artemisinin resistance evolved very rapidly up to extreme, near-lethal doses of artesunate (240 mg/kg), an increase of > 3000-fold in the effective in vivo dose, far above resistance levels reported from the field. Artemisinin resistance selection was reproducible, occurring in 80% and 41% of mice treated with flash-dose and 2-day regimens, respectively, and the resistance phenotype was stable. Measuring in vitro sensitivity proved inappropriate as an early marker of resistance, as IC50 remained stable despite in vivo resistance up to 30 mg/kg (ART-S: 10.7 nM (95% CI 10.2–11.2) vs. ART-R30: 11.5 nM (6.6–16.9), F = 0.525, p = 0.47). However, when in vivo resistance strengthened further, IC50 increased 10-fold (ART-R240 100.3 nM (92.9–118.4), F = 304.8, p
Published: 2018

21. Cwp19 Is a Novel Lytic Transglycosylase Involved in Stationary-Phase Autolysis Resulting in Toxin Release in Clostridium difficile

Author: Jean-Louis Pons, Bruno Dupuy, Marie-Pierre Chapot-Chartier, Marie-José Butel, Imane El Meouche, Sandra Wydau-Dematteis, René Lai-Kuen, Johann Peltier, Audrey Hamiot, François Fenaille, Bruno Saubaméa, Pascal Courtin, Ecosystème intestinal, probiotiques, antibiotiques (EA 4065), Université Paris Descartes - Paris 5 (UPD5), Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7), Plateau technique Imagerie Cellulaire et Moléculaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), This work was supported by the University of Rouen and the University of Paris-Descartes. J. Peltier is funded by a Pasteur-Roux fellowship. The work of P. Courtin andM.-P. Chapot-Chartier was supported by INRA., Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Peltier, Johann, and Martin, Marie
Subjects: autolysins, lytic transglycosylase, peptidoglycan, surface proteins, toxins, clostridium difficile, 0301 basic medicine, autolysin, Autolysis (biology), toxins secretion, peptidoglycan hydrolase, Applied Microbiology, MESH: Catalytic Domain, medicine.disease_cause, Cwp19, chemistry.chemical_compound, Cell Wall, Catalytic Domain, glucose, MESH: Bacterial Proteins, MESH: Gene Expression Regulation, Bacterial, Chemistry, Cell autolysis, Clostridium difficile, QR1-502, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Lytic cycle, MESH: Peptidoglycan Glycosyltransferase, Research Article, MESH: Bacteriolysis, MESH: Clostridium Infections, 030106 microbiology, Microbiology, 03 medical and health sciences, Bacteriolysis, MESH: Cell Wall, Bacterial Proteins, Virology, Genetics, medicine, Humans, Secretion, Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Clostridium difficile, MESH: Humans, Clostridioides difficile, Toxin, Lytic transglycosylase activity, Gene Expression Regulation, Bacterial, Clostridium Infections, Peptidoglycan Glycosyltransferase, Peptidoglycan
Abstract: Clostridium difficile is the major etiologic agent of antibiotic-associated intestinal disease. Pathogenesis of C. difficile is mainly attributed to the production and secretion of toxins A and B. Unlike most clostridial toxins, toxins A and B have no signal peptide, and they are therefore secreted by unusual mechanisms involving the holin-like TcdE protein and/or autolysis. In this study, we characterized the cell surface protein Cwp19, a newly identified peptidoglycan-degrading enzyme containing a novel catalytic domain. We purified a recombinant His6-tagged Cwp19 protein and showed that it has lytic transglycosylase activity. Moreover, we observed that Cwp19 is involved in cell autolysis and that a C. difficile cwp19 mutant exhibited delayed autolysis in stationary phase compared to the wild type when bacteria were grown in brain heart infusion (BHI) medium. Wild-type cell autolysis is correlated to strong alterations of cell wall thickness and integrity and to release of cytoplasmic material. Furthermore, we demonstrated that toxins were released into the extracellular medium as a result of Cwp19-induced autolysis when cells were grown in BHI medium. In contrast, Cwp19 did not induce autolysis or toxin release when cells were grown in tryptone-yeast extract (TY) medium. These data provide evidence for the first time that TcdE and bacteriolysis are coexisting mechanisms for toxin release, with their relative contributions in vitro depending on growth conditions. Thus, Cwp19 is an important surface protein involved in autolysis of vegetative cells of C. difficile that mediates the release of the toxins from the cell cytosol in response to specific environment conditions., IMPORTANCE Clostridium difficile-associated disease is mainly known as a health care-associated infection. It represents the most problematic hospital-acquired infection in North America and Europe and exerts significant economic pressure on health care systems. Virulent strains of C. difficile generally produce two toxins that have been identified as the major virulence factors. The mechanism for release of these toxins from bacterial cells is not yet fully understood but is thought to be partly mediated by bacteriolysis. Here we identify a novel peptidoglycan hydrolase in C. difficile, Cwp19, exhibiting lytic transglycosylase activity. We show that Cwp19 contributes to C. difficile cell autolysis in the stationary phase and, consequently, to toxin release, most probably as a response to environmental conditions such as nutritional signals. These data highlight that Cwp19 constitutes a promising target for the development of new preventive and curative strategies.
Published: 2018

22. Tacrolimus diffusion across the peripheral mononuclear blood cell membrane: impact of drug transporters

Author: Julie Querzerho-Raguideau, Yves Deugnier, Benoit Blanchet, Camille Tron, Marie Allard, Jerome Le Priol, Marie-José Ferrand-Sorre, Marie-Clémence Verdier, Mickael Roussel, Eric Bellissant, Florian Lemaitre, Antoine Petitcollin, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), UF Pharmacocinétique et Pharmacochimie [AP-HP Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Jonchère, Laurent
Subjects: Time Factors, chemical and pharmacologic phenomena, Pharmacology, 030226 pharmacology & pharmacy, Peripheral blood mononuclear cell, Mass Spectrometry, Tacrolimus, 03 medical and health sciences, 0302 clinical medicine, stomatognathic system, medicine, Humans, Pharmacology (medical), calcineurin, ComputingMilieux_MISCELLANEOUS, Whole blood, membrane transporter, medicine.diagnostic_test, Chemistry, diffusion, Cell Membrane, Temperature, Biological Transport, peripheral blood mononuclear cells, Calcineurin, Probenecid, stomatognathic diseases, Therapeutic drug monitoring, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Leukocytes, Mononuclear, Verapamil, Efflux, Drug Monitoring, 030217 neurology & neurosurgery, Ex vivo, Biomarkers, Immunosuppressive Agents, medicine.drug, Chromatography, Liquid
Abstract: Measuring tacrolimus (TAC) concentration in peripheral blood mononuclear cells (PBMCs) could better reflect the drug effect on its target (calcineurin (CaN) in lymphocytes) than whole blood concentrations. Mechanisms influencing TAC diffusion into PBMC are not well characterized. This work aimed at describing, ex vivo, TAC diffusion kinetics into PBMC and investigating the contribution of membrane transporters to regulate TAC intracellular concentration as well as the impact on CaN activity. PBMCs were incubated with TAC for 5 min to 4 h and under several experimental conditions: 37 °C (physiological conditions), 4 °C (inhibition of influx and efflux active transport), 37 °C + transporter inhibitors (verapamil, carvedilol, and probenecid and bromosulfophthalein, respectively, inhibitors of P-gp, OAT, and OATP). TAC concentration and CaN activity were measured in PBMC using liquid chromatography coupled with mass spectrometry. TAC intra-PBMC concentration was maximal after 1 h of incubation. Mean TAC PMBC concentrations were significantly lower in samples incubated at 4 °C compared to the 37 °C groups. Addition of verapamil slightly increased TAC accumulation in PBMC while other inhibitors had no effect. A significant correlation was found between TAC intra-PBMC concentration and the level of inhibition of CaN. Using an ex vivo cellular model, these results suggest that P-gp is involved in the drug efflux from PBMC while influx active transporters likely to regulate TAC intra-PBMC disposition remain to be identified. TAC concentration in PBMC is correlated with its pharmacodynamic effect. Then, TAC intra-PBMC concentration appears to be a promising biomarker to refine TAC therapeutic drug monitoring.
Published: 2018

23. Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition

Author: Stéphanie Arnould, Geneviève Rodier, Jean Noel, Charlene Berthet, Simon Lachambre, Charles Vincent, Pierre-Olivier Vidalain, Florence Bernex, Marta Jarlier, Nelly Pirot, Yoan Buscail, Charles Theillet, Claude Sardet, Yoann Delorme, Yves L. Janin, Gisèle Matar, Hélène Delpech, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), MRI-Montpellier RIO Imaging, Génétique Moléculaire et Cellulaire (UGMC), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Chimie et Biocatalyse, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Programmed cell death, Cell, Chk1, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, chemistry.chemical_compound, Teriflunomide, medicine, CHEK1, Cytotoxicity, Caspase, biology, DHODH, Molecular biology, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, chemistry, Cell culture, triple negative breast cancer, biology.protein, Dihydroorotate dehydrogenase, DNA damage, cytotoxicity, Research Paper
Abstract: International audience; Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalised counterparts, and this effect was amplified when cells were subsequently exposed to PF477736 Chk1 inhibitor. Flow cytometry analyses revealed substantial accumulations of cells in S and G2/M phases, followed by increased cytotoxicity which was characterised by caspase 3-dependent induction of cell death. Associating PF477736 with teriflunomide also significantly sensitised SUM159 and HCC1937 human triple negative breast cancer cell lines to dihydroorotate dehydrogenase inhibition. The main characteristic of this effect was the sustained accumulation of teriflunomide-induced DNA damage as cells displayed increased phospho serine 139 H2AX (γH2AX) levels and concentration-dependent phosphorylation of Chk1 on serine 345 upon exposure to the combination as compared with either inhibitor alone. Importantly a similar significant increase in cell death was observed upon dual siRNA mediated depletion of Chk1 and DHODH in both murine and human cancer cell models. Altogether these results suggest that combining DHODH and Chk1 inhibitions may be a strategy worth considering as a potential alternative to conventional chemotherapies.
Published: 2017

24. Trial Watch: Adoptively transferred cells for anticancer immunotherapy

Author: François Martin, Guido Kroemer, Lorenzo Galluzzi, Lionel Apetoh, Laurence Zitvogel, Carole Fournier, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska Institutet [Stockholm], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, PD-L1, Adoptive cell transfer, Breakthrough therapy, medicine.medical_treatment, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Biology, cytotoxic T lymphocyte, lcsh:RC254-282, CD19, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Antigen, PD-1, medicine, Immunology and Allergy, Cytotoxic T cell, NK cell, chimeric antigen receptor, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Chimeric antigen receptor, 3. Good health, immune checkpoint blockers, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, lcsh:RC581-607
Abstract: IF 7.719; International audience; Immunotherapies aimed at strengthening immune effector responses against malignant cells are growing at exponential rates. Alongside, the impressive benefits obtained by patients with advanced melanoma who received adoptively transferred tumor-infiltrating lymphocytes (TILs) have encouraged the scientific community to pursue adoptive cell transfer (ACT)-based immunotherapy. ACT involves autologous or allogenic effector lymphocytes that are generally obtained from the peripheral blood or resected tumors, expanded and activated ex vivo, and administered to lymphodepleted patients. ACT may be optionally associated with chemo- and/or immunotherapeutics, with the overall aim of enhancing the proliferation, persistence and functionality of infused cells, as well as to ensure their evolution in an immunological permissive local and systemic microenvironment. In addition, isolated lymphocytes can be genetically engineered to endow them with the ability to target a specific tumor-associated antigen (TAA), to increase their lifespan, and/or to reduce their potential toxicity. The infusion of chimeric antigen receptor (CAR)-expressing cytotoxic T lymphocytes redirected against CD19 has shown promising clinical efficacy in patients with B-cell malignancies. Accordingly, the US Food and Drug Administration (FDA) has recently granted 'breakthrough therapy' designation to a CAR-based T-cell therapy (CTL019) for patients with B-cell malignancies. Considerable efforts are now being devoted to the development of efficient ACT-based immunotherapies for non-hematological neoplasms. In this Trial Watch, we summarize recent clinical advances on the use of ACT for oncological indications.
Published: 2017

25. Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface

Author: Alice Gilbert, Nicolas Adam, Noémie Mazaré, Fabrice Chrétien, Mathieu Bahin, Stéphanie Chasseigneaux, Martine Cohen-Salmon, Corinne Blugeon, Sandrine Perrin, Bruno Saubaméa, Jean-Louis Laplanche, Stéphane Le Crom, Xavier Declèves, Juliette Pouch, Anne-Cécile Boulay, Bertrand Ducos, Leïla Bastianelli, Auguste Genovesio, Decleves, Xavier, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Plates-formes mutualisées du centre de recherche pharmaceutique de Paris (P-MIM - UMS 3612), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris] (IP), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GenomiqueENS (Genomique ENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Laboratoire de Physique Statistique de l'ENS (LPS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Analyse des Données à Haut Débit en Génomique (ADHDG), Evolution Paris Seine, Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), This work was supported by Fondation pour la Recherche Médicale (FRM), the Labex MemoLife, and Fondation Gueules Cassées. The Ecole normale supérieure genomic platform was supported by the France Génomique national infrastructure, funded as part of the 'Investissements d'Avenir' program managed by the Agence Nationale de la Recherche (contract ANR-10-INBS-09)., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Plateforme Génomique de l'IBENS, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (... - 2019) (UNS), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Bioinformatics, Biochemistry, Article, 03 medical and health sciences, symbols.namesake, astrocyte, local translation, 0302 clinical medicine, translating ribosome immunoprecipitation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Protein biosynthesis, medicine, Molecular Biology, mRNAs localization, Chemistry, Endoplasmic reticulum, Translation (biology), Cell Biology, Golgi apparatus, Translocon, endfeet, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Secretory protein, Membrane protein, symbols, gliovascular unit, 030217 neurology & neurosurgery, Astrocyte
Abstract: Astrocytes send out long processes that are terminated by endfeet at the vascular surface and regulate vascular functions as well as homeostasis at the vascular interface. To date, the astroglial mechanisms underlying these functions have been poorly addressed. Here we demonstrate that a subset of messenger RNAs is distributed in astrocyte endfeet. We identified, among this transcriptome, a pool of messenger RNAs bound to ribosomes, the endfeetome, that primarily encodes for secreted and membrane proteins. We detected nascent protein synthesis in astrocyte endfeet. Finally, we determined the presence of smooth and rough endoplasmic reticulum and the Golgi apparatus in astrocyte perivascular processes and endfeet, suggesting for local maturation of membrane and secreted proteins. These results demonstrate for the first time that protein synthesis occurs in astrocyte perivascular distal processes that may sustain their structural and functional polarization at the vascular interface.
Published: 2017

26. Reemergence of chloroquine-sensitive pfcrt K76 Plasmodium falciparum genotype in southeastern Cameroon

Author: Martine Peeters, Leonardo K. Basco, Eitel Mpoudi Ngolle, Philippe Deloron, Nicaise Tuikue Ndam, Rachida Tahar, Ahidjo Ayouba, Vincent Foumane Ngane, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), PRES Sorbonne Paris Cité, Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Noguchi Memorial Institute for Medical Research [Accra, Ghana] (NMIMR), University of Ghana, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche sur le Paludisme [Yaoundé, Cameroon], Organisation de Coordination pour la lutte contre les Endémies en Afrique Centrale, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Prévention du Sida au Cameroun [Yaoundé, Cameroon], Institut de Recherches Médicales et d’Études des Plantes Médicinales [Yaoundé, Cameroon] (IMPM), This work was supported by the French Agence Nationale de la Recherche (ANR, Programme Blanc 2011, SVSE3, PRIMAL) and the French Ministry of Research (Programme PAL+)., Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), COMBE, Isabelle, Mère et enfant face aux infections tropicales ( MERIT - UMR_D 216 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut de Recherche pour le Développement ( IRD ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Noguchi Memorial Institute for Medical Research [Accra, Ghana], Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes ( URMITE ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR48, INSB-INSB-Centre National de la Recherche Scientifique ( CNRS ), Recherches Translationnelles sur le VIH et les maladies infectieuses ( TransVIHMI ), Université de Montpellier ( UM ) -Universtié Yaoundé 1 [Cameroun]-Université Cheikh Anta Diop ( UCAD ) -Université Montpellier 1 ( UM1 ) -Institut de Recherche pour le Développement ( IRD ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Recherches Médicales et d’Études des Plantes Médicinales [Yaoundé, Cameroon] ( IMPM ), INSB-INSB-Centre National de la Recherche Scientifique (CNRS), and Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Subjects: 0301 basic medicine, Male, Drug Resistance, Protozoan Proteins, 0302 clinical medicine, Chloroquine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cameroon, Artemisinin, Malaria, Falciparum, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, education.field_of_study, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, [ SDV.MHEP.ME ] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious Diseases, Child, Preschool, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, medicine.drug, [ SDV.MP.PAR ] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:Arctic medicine. Tropical medicine, Genotype, lcsh:RC955-962, 030231 tropical medicine, 030106 microbiology, Population, Plasmodium falciparum, Amodiaquine, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Antimalarials, parasitic diseases, medicine, Humans, lcsh:RC109-216, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, education, Research, Haplotype, Infant, Membrane Transport Proteins, Molecular markers, medicine.disease, biology.organism_classification, Virology, Parasitology, Drug resistance, Immunology, Malaria
Abstract: International audience; Background: Chloroquine had been used extensively during the last five decades in Cameroon. Its decreasing clinical effectiveness, supported by high proportions of clinical isolates carrying the mutant pfcrt haplotype (CVIET), led the health authorities to resort to amodiaquine monotherapy in 2002 and artemisinin-based combination therapy (ACT) in 2004 (artesunate-amodiaquine, with artemether-lumefantrine as an alternative since 2006) as the first-line treatment of uncomplicated malaria. The aim of the present study was to investigate whether the withdrawal of chloroquine was associated with a reduction in pfcrt mutant parasite population and reemergence of chloroquinesensitive parasites in southeastern Cameroon between 2003 and 2012.Methods: The frequency of pfcrt haplotypes at positions 72-76 in Plasmodium falciparum isolates collected from individuals in 2003 and 2012 in southeastern Cameroon was determined by sequence specific oligonucleotide probes-enzyme linked immunosorbent assay (SSOP-ELISA). Results: The proportions of parasites carrying the mutant haplotype CVIET and the wild-type CVMNK were 53.0 and 28.0% in 2003, respectively. The proportion of the mutant haplotype in samples collected 9 years later decreased to 25.3% whereas the proportion of parasites carrying the wild-type CVMNK haplotype was 53.7%.Conclusions: Even though the proportion of chloroquine-sensitive parasites seems to be increasing in southeastern Cameroon, a reintroduction of chloroquine cannot be recommended at present in Cameroon. The current national anti-malarial drug policy should be implemented and reinforced to combat drug-resistant malaria.
Published: 2017

27. Intestinal invalidation of the glucose transporter GLUT2 delays tissue distribution of glucose and reveals an unexpected role in gut homeostasis

Author: Charlotte Schmitt, Chloé Melchior, Ophélie Rouxel, Thomas Aranias, Danielle Chateau, Guillaume Gourcerol, Armelle Leturque, Alexandra Grosfeld, Agnès Lehuen, Edith Brot-Laroche, Maude Le Gall, Patricia Serradas, Nathalie Kapel, Anne-Judith Waligora-Dupriet, Thomas Viel, Bertrand Tavitian, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Service d'Hépato-Gastroentérologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), LabEx Inflamex, Service de coprologie fonctionnelle, CHU Pitié-Salpêtrière [APHP], Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de physiologie digestive, urinaire, respiratoire et de l'exercice [CHU Rouen], Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), HAL UPMC, Gestionnaire, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: Blood Glucose, 0301 basic medicine, Malabsorption, OGTT, oral glucose tolerance test, Glucose Transport Proteins, Facilitative, Gut flora, Glucose homeostasis, Mice, 0302 clinical medicine, Glucagon-Like Peptide 1, PET-CT, Positron Emission Tomography-Computed Tomography, Homeostasis, Tissue Distribution, Sodium-Glucose Transporter 1, Intestinal Mucosa, IEC, intestinal epithelial cells, ComputingMilieux_MISCELLANEOUS, Glucose Transporter Type 2, Mice, Knockout, 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology, Microbiota, GLP-1, glucagon-like peptide-1, GLUT1-7, glucose transporter 1–7, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Glucose-galactose malabsorption, IPGTT, intraperitoneal glucose tolerance test, Original Article, medicine.medical_specialty, lcsh:Internal medicine, endocrine system, Calorie restriction, Intestinal adaptation, 030209 endocrinology & metabolism, digestive system, DPP-IV, dipeptidyl-peptidase IV, 03 medical and health sciences, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:RC31-1245, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 2FDG, 2-deoxy-2-[18F]fluoro-d-glucose, ITT, insulin tolerance test, Glucose transporter, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, biology.organism_classification, medicine.disease, IL, interleukin, SGLT1, sodium-glucose transporter 1, Glucose, 030104 developmental biology, Endocrinology, Intestinal Absorption, biology.protein, GLUT2, GLP-1
Abstract: Objective Intestinal glucose absorption is orchestrated by specialized glucose transporters such as SGLT1 and GLUT2. However, the role of GLUT2 in the regulation of glucose absorption remains to be fully elucidated. Methods We wanted to evaluate the role of GLUT2 on glucose absorption and glucose homeostasis after intestinal-specific deletion of GLUT2 in mice (GLUT2ΔIEC mice). Results As anticipated, intestinal GLUT2 deletion provoked glucose malabsorption as visualized by the delay in the distribution of oral sugar in tissues. Consequences of intestinal GLUT2 deletion in GLUT2ΔIEC mice were limiting body weight gain despite normal food intake, improving glucose tolerance, and increasing ketone body production. These features were reminiscent of calorie restriction. Other adaptations to intestinal GLUT2 deletion were reduced microvillus length and altered gut microbiota composition, which was associated with improved inflammatory status. Moreover, a reduced density of glucagon-like peptide-1 (GLP-1) positive cells was compensated by increased GLP-1 content per L-cell, suggesting a preserved enteroendocrine function in GLUT2ΔIEC mice. Conclusions Intestinal GLUT2 modulates glucose absorption and constitutes a control step for the distribution of dietary sugar to tissues. Consequently, metabolic and gut homeostasis are improved in the absence of functional GLUT2 in the intestine, thus mimicking calorie restriction., Highlights • Intestinal GLUT2 deletion induces moderate malabsorption and ketone body production. • Loss of intestinal GLUT2 modulates gut microbiota. • Intestinal GLUT2 plays a role in gut permeability and inflammatory status. • Intestinal GLUT2 modulates enteroendocrine L-cell function.
Published: 2017

28. Defective signaling through plexin-A1 compromises the development of the peripheral olfactory system and neuroendocrine reproductive axis in mice

Author: Jean-Pierre Hardelin, Corinne Fouveaut, Catherine Dodé, Fabrice Ango, Séverine Marcos, Nelly Pitteloud, Xavier Rovira, Carine Monnier, Universitat de Vic - Universitat Central de Catalunya. Grup de recerca en Reparació i Regeneració Tissular (TR2Lab), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut Pasteur [Paris], Agence Nationale pour la Recherche (grant number ANR-14-CE12-0015 to S.M., C.M., F.A., C.D., and J.-P.H.), We thank the patients for their contribution to the study. We also thank the animal platform (CRP2, CNRS UMS3612, Inserm US25, Paris-Descartes University) for housing of the mice., ANR-14-CE12-0015,RoSes and GnRH,La signalisation cellulaire par les sémaphorines dans le contrôle neuroendocrinien de la reproduction(2014), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and CHU Cochin [AP-HP]
Subjects: Male, 0301 basic medicine, Olfactory system, Kallmann syndrome, [SDV]Life Sciences [q-bio], Semaphorins, Gonadotropin-releasing hormone, medicine.disease_cause, Gonadotropin-Releasing Hormone, Mice, 0302 clinical medicine, Cell Movement, Genetics (clinical), Neurons, Mutation, Genètica humana, biology, Reproduction, Oligogenic Inheritance, General Medicine, Olfactory Bulb, 3. Good health, Female, Síndrome de Kallmann, Signal Transduction, Adult, Heterozygote, medicine.medical_specialty, Cell signaling, Hypothalamus, Nerve Tissue Proteins, Receptors, Cell Surface, 03 medical and health sciences, Neuroendocrine Cells, Semaphorin, Internal medicine, Genetics, medicine, Animals, Humans, Molecular Biology, Hypogonadism, Plexin, Semaphorin-3A, Kallmann Syndrome, medicine.disease, 030104 developmental biology, Endocrinology, biology.protein, 030217 neurology & neurosurgery
Abstract: The olfacto-genital syndrome (Kallmann syndrome) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. This is a genetically heterogeneous developmental disease with various modes of transmission, including oligogenic inheritance. Previous reports have involved defective cell signaling by semaphorin-3A in the disease pathogenesis. Here, we report that the embryonic phenotype of Plxna1-/- mutant mice lacking plexin-A1 (a major receptor of class 3 semaphorins), though not fully penetrant, resembles that of Kallmann syndrome fetuses. Pathohistological analysis indeed showed a strongly abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the hypothalamic brain region in some of the mutant mice, which resulted in reduced fertility in adult males. We thus screened 250 patients for the presence of mutations in PLXNA1, and identified different nonsynonymous mutations (p.V349L, p.V437L, p.R528W, p.H684Y, p.G720E, p.R740H, p.R813H, p.R840Q, p.A854T, p.R897H, p.L1464V, p.K1618T, p.C1744F), all at heterozygous state, in 15 patients. Most of these mutations are predicted to affect plexin-A1 stability or signaling activity based on predictive algorithms and a structural model of the protein. Moreover, in vitro experiments allowed us to show the existence of deleterious effects of eight mutations (including a transcript splicing defect), none of which are expected to result in a complete loss of protein synthesis, targeting, or signaling activity, though. Our findings indicate that signaling insufficiency through plexin-A1 can contribute to the pathogenesis of Kallmann syndrome, and further substantiate the oligogenic pattern of inheritance in this developmental disorder.
Published: 2017

29. Influence of host factors and parasite biomass on the severity of imported Plasmodium falciparum malaria

Author: Nicolas Argy, Sandrine Cojean, Jérôme Clain, Claire Augé-Courtoi, Pascal Houzé, Philippe Deloron, Eric Kendjo, Véronique Hubert, Sandrine Houzé, Marc Thellier, Centre National de Référence du Paludisme, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Service de Parasitologie Mycologie [AP-HP Hôpital Bichat - Claude Bernard], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Laboratoire de pharmacologie [CHU St Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Mère et enfant face aux infections tropicales ( MERIT - UMR_D 216 ), Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: Male, Plasmodium, Epidemiology, Protozoan Proteins, lcsh:Medicine, Antibodies, Protozoan, Pathology and Laboratory Medicine, Severity of Illness Index, 0302 clinical medicine, Mathematical and Statistical Techniques, Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Parasite hosting, 030212 general & internal medicine, Biomass, Malaria, Falciparum, Enzyme-Linked Immunoassays, lcsh:Science, Protozoans, education.field_of_study, Multidisciplinary, Malarial Parasites, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Middle Aged, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Serology, Physical Sciences, Female, France, Antibody, Statistics (Mathematics), Research Article, Adult, medicine.medical_specialty, 030231 tropical medicine, Population, Plasmodium falciparum, Antigens, Protozoan, macromolecular substances, Biology, Research and Analysis Methods, Host-Parasite Interactions, 03 medical and health sciences, Young Adult, Antigen, Severity of illness, Parasite Groups, parasitic diseases, medicine, Parasitic Diseases, Humans, Statistical Methods, education, Immunoassays, Demography, lcsh:R, Organisms, Biology and Life Sciences, biology.organism_classification, medicine.disease, Tropical Diseases, Parasitic Protozoans, Malaria, Logistic Models, Immunology, Multivariate Analysis, biology.protein, Immunologic Techniques, lcsh:Q, Parasitology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Apicomplexa, Mathematics
Abstract: Objectives Imported malaria in France is characterized by various clinical manifestations observed in a heterogeneous population of patients such as travelers/expatriates and African migrants. In this population, host factors and parasite biomass associated with severe imported malaria are poorly known. Methods From data collected by the Centre National de Reference du Paludisme, we identified epidemiological, demographic and biological features including parasite biomass and anti-plasmodial antibody levels (negative, positive and strongly positive serology) associated with different disease severity groups (very severe, moderately severe, and uncomplicated malaria) in 3 epidemiological groups (travelers/expatriates, first- and second-generation migrants). Results Age, ethnicity, absence of prior infection with P. falciparum, antibody levels, plasma PfHRP2 levels, total and circulating parasite biomass were related to severe malaria onset. Sequestered parasite biomass tended to be increased in very severe malaria, and was strongly correlated to the antibody level of the host. Conclusions Prior exposure to P. falciparum is associated with high anti-plasmodial antibody levels which influence clinical presentation of imported malaria and its correlated circulating and sequestered parasite burden.
Published: 2017

30. Ceramides and sphingomyelinases in senile plaques

Author: Luce Dauphinot, Maï Panchal, Olivier Laprévote, Massimo Masserini, Isabelle Rivals, Charles Duyckaerts, Adina N. Lazar, Delphine Dargère, Nicolas Auzeil, Sophie Ayciriex, Elisa Salvati, Mathieu Gaudin, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Géosciences Marines (GM), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Neurobiologie, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Panchal, M, Gaudin, M, Lazar, A, Salvati, E, Rivals, I, Ayciriex, S, Dauphinot, L, Dargère, D, Auzeil, N, Masserini, M, Laprévote, O, Duyckaerts, C, Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), ICNS - Institut de Chimie des Substances naturelles, Unité de recherche Géosciences Marines (Ifremer) ( GM ), Institut Français de Recherche pour l'Exploitation de la Mer ( IFREMER ), Equipe de Statistique Appliquée ( ESA ), ESPCI ParisTech, ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Unité de recherche Géosciences Marines (Ifremer) (GM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Equipe de Statistique Appliquée (ESA), ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]
Subjects: Male, Amyloid beta-Peptide, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Plaque, Amyloid, Ceramide, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 0302 clinical medicine, Senile plaques, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Lipid, Middle Aged, Lipidome, BIO/10 - BIOCHIMICA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Sphingomyelin Phosphodiesterase, medicine.anatomical_structure, Neurology, Biochemistry, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Female, Alzheimer's disease, Alzheimer disease, Sphingomyelin, Microdissection, Human, Electrospray ionization, Fibril, Ceramides, lcsh:RC321-571, 03 medical and health sciences, Apolipoproteins E, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Aβ peptide, Lipidomics, Neuropil, medicine, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Aged, 030304 developmental biology, Amyloid beta-Peptides, Senile plaque, Mass spectrometry, Lipidomic, Surface Plasmon Resonance, medicine.disease, Molecular biology, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, Sphingomyelinase, Laser microdissection, 030217 neurology & neurosurgery, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Chromatography, Liquid
Abstract: The senile plaque is a hallmark lesion of Alzheimer disease (AD). We compared, without a priori, the lipidome of the senile plaques and of the adjacent plaque-free neuropil. The analysis by liquid chromatography coupled with electrospray ionization mass spectrometry revealed that laser microdissected senile plaques were enriched in saturated ceramides Cer(d18:1/18:0) and Cer(d18:1/20:0) by 33 and 78% respectively with respect to the surrounding neuropil. This accumulation of ceramides was not explained by their affinity for Aβ deposits: no interaction between ceramide-liposomes and Aβ fibrils was observed in vitro by surface plasmon resonance and fluorescent ceramide-liposomes showed no affinity for the senile plaques in AD brain tissue. Accumulation of ceramides could be, at least partially, the result of a local production by acid and neutral sphingomyelinases that we found to be present in the corona of the senile plaques. © 2014 Elsevier Inc.
Published: 2014

31. In Vitro Analysis of the Interaction between Atovaquone and Proguanil against Liver Stage Malaria Parasites

Author: Jean-François Franetich, Lídia Barata, Gigliola Zanghi, Pascal Houzé, Jérôme Clain, Dominique Mazier, Khadija Boutbibe, Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de recherche pour le développement ( IRD [Burkina Faso] ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre National de Référence du Paludisme [CHU Pitié-Salpétrière], Centre National de Référence du Paludisme, PRES Sorbonne Paris Cité-APHP-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Institut de recherche pour le développement (IRD [Burkina Faso]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-PRES Sorbonne Paris Cité, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Drug, Cycloguanil, Proguanil, media_common.quotation_subject, Plasmodium falciparum, Pharmacology, 03 medical and health sciences, Antimalarials, Inhibitory Concentration 50, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, medicine, Humans, Pharmacology (medical), Malaria, Falciparum, Atovaquone, media_common, biology, Triazines, biology.organism_classification, medicine.disease, In vitro, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Combinations, 030104 developmental biology, Infectious Diseases, Liver, Hepatocytes, human activities, Plasmodium yoelii, Malaria, medicine.drug
Abstract: The interaction between atovaquone and proguanil has never been studied against liver stage malaria, which is the main target of this drug combination when used for chemoprevention. Using human hepatocytes lacking cytochrome P450 activity, and thus avoiding proguanil metabolizing into potent cycloguanil, we show in vitro that the atovaquone-proguanil combination synergistically inhibits the growth of rodent Plasmodium yoelii parasites. These results provide a pharmacological basis for the high efficacy of atovaquone-proguanil used as malaria chemoprevention.
Published: 2016

32. The antimalarial drug primaquine targets Fe–S cluster proteins and yeast respiratory growth

Author: Jérôme Clain, Grzegorz Pawlik, Marie-Pierre Golinelli-Cohen, Brigitte Meunier, Zehua Song, Cindy Vallières, Cécile Bouton, Sarah M. Tindall, Simon V. Avery, Anaïs Laleve, Biogenèse et fonctionnement des complexes OXPHOS mitochondriaux (BIOMIT), Département Biologie Cellulaire (BioCell), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), School of Life Sciences, University of Nottingham, UK (UON), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Biogenèse et fonctionnement des complexes OXPHOS mitochondriaux ( BIOMIT ), Département Biologie Cellulaire ( BioCell ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), University of Nottingham, UK ( UON ), Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: 0301 basic medicine, Saccharomyces cerevisiae Proteins, Primaquine, [SDV]Life Sciences [q-bio], Clinical Biochemistry, SOD2, Saccharomyces cerevisiae, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Biology, Biochemistry, Aconitase, Mitochondria, Malaria, Aconitase, Sod2, Oxidative stress, Yeast model, Primaquine, Superoxide dismutase, Antimalarials, Gene Knockout Techniques, 03 medical and health sciences, Gene Expression Regulation, Fungal, medicine, Respiratory function, lcsh:QH301-705.5, Yeast model, Aconitate Hydratase, lcsh:R5-920, 030102 biochemistry & molecular biology, [ SDV ] Life Sciences [q-bio], Superoxide Dismutase, Organic Chemistry, Plasmodium falciparum, Sod2, biology.organism_classification, 3. Good health, Mitochondria, Malaria, 030104 developmental biology, lcsh:Biology (General), Mechanism of action, Oxidative stress, biology.protein, ATP-Binding Cassette Transporters, medicine.symptom, lcsh:Medicine (General), Cytochrome-B(5) Reductase, Research Paper, Molecular Chaperones, medicine.drug
Abstract: Malaria is a major health burden in tropical and subtropical countries. The antimalarial drug primaquine is extremely useful for killing the transmissible gametocyte forms of Plasmodium falciparum and the hepatic quiescent forms of P. vivax. Yet its mechanism of action is still poorly understood. In this study, we used the yeast Saccharomyces cerevisiae model to help uncover the mode of action of primaquine. We found that the growth inhibitory effect of primaquine was restricted to cells that relied on respiratory function to proliferate and that deletion of SOD2 encoding the mitochondrial superoxide dismutase severely increased its effect, which can be countered by the overexpression of AIM32 and MCR1 encoding mitochondrial enzymes involved in the response to oxidative stress. This indicated that ROS produced by respiratory activity had a key role in primaquine-induced growth defect. We observed that Δsod2 cells treated with primaquine displayed a severely decreased activity of aconitase that contains a Fe–S cluster notoriously sensitive to oxidative damage. We also showed that in vitro exposure to primaquine impaired the activity of purified aconitase and accelerated the turnover of the Fe–S cluster of the essential protein Rli1. It is suggested that ROS-labile Fe–S groups are the primary targets of primaquine. Aconitase activity is known to be essential at certain life-cycle stages of the malaria parasite. Thus primaquine-induced damage of its labile Fe–S cluster – and of other ROS-sensitive enzymes – could inhibit parasite development., Graphical abstract fx1, Highlights • The mode of action of the antimalarial drug primaquine is poorly understood. • The yeast model is used to decipher its mechanism of action. • SOD and respiratory function are key for yeast sensitivity to primaquine. • Primaquine treatment impairs Fe–S containing enzyme aconitase. • Its attack on Fe–S clusters could explain the primaquine-induced growth inhibition.
Published: 2016

33. Update on infections with human herpesviruses 6A, 6B, and 7

Author: Agut, H., Bonnafous, P., Gautheret-Dejean, A., Service de Virologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Service de virologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: viruses, Intégration chromosomique, Infections opportunistes, virus diseases, biochemical phenomena, metabolism, and nutrition, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Exanthema subitum, HHV-6, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, HHV-7, Exanthème subit, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chromosomal integration, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Opportunistic infections
Abstract: International audience; Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7) are genetically related to cytomegalovirus. They belong to the Roseolovirus genus and to the Betaherpesvirinae subfamily. They infect T cells, monocytes-macrophages, epithelial cells, and central nervous system cells. These viruses are ubiquitous and are responsible for lifelong chronic infections, most often asymptomatic, in the vast majority of the general adult population. HHV-6B is responsible for exanthema subitum, which is a benign disease of infants. HHV-6A and HHV-6B also cause opportunistic infections in immunocompromised patients: encephalitis, hepatitis, bone marrow suppression, colitis, and pneumonitis. Their etiological role in chronic diseases such as multiple sclerosis, cardiomyopathy, and thyroiditis is still controversial. The pathogenicity of HHV-7 is less clear and seems to be much more restricted. Chromosomal integration of HHV-6A and HHV-6B is transmissible from parents to offspring and observed in about 1% of the general population. This integration raises the question of potential associated diseases and can be a confounding factor for the diagnosis of active infections by both viruses. The diagnosis of HHV-6A, HHV-6B, and HHV-7 infections is rather based on gene amplification (PCR), which allows for the detection and quantification of the viral genome, than on serology, which is mainly indicated in case of primary infection. Ganciclovir, foscarnet, and cidofovir inhibit the replication of HHV-6A, HHV-6B, and HHV-7. Severe infections may thus be treated but these therapeutic indications are still poorly defined.; Les herpesvirus humains 6A, 6B et 7 (HHV-6A, HHV-6B, HHV-7) sont génétiquement proches du cytomégalovirus. Ils appartiennent au genre des Roseolovirus et à la sous-famille des Betaherpesvirinae. Ils infectent les lymphocytes T, mais aussi les monocytes/macrophages, certaines cellules épithéliales et les cellules du système nerveux central. Ces virus sont ubiquistes et provoquent une infection chronique à vie, le plus souvent asymptomatique, chez la quasi-totalité de la population générale adulte. Le HHV-6B est responsable de l’exanthème subit, maladie bénigne du très jeune enfant. Les HHV-6A et HHV-6B sont responsables d’infections opportunistes chez les patients immunodéprimés : encéphalites, hépatites, insuffisances médullaires, colites et pneumopathies. Leur rôle étiologique dans des maladies chroniques comme sclérose en plaques, myocardiopathies ou thyroïdites est encore controversé. La pathogénicité du HHV-7 est moins bien connue et paraît beaucoup plus restreinte. L’intégration chromosomique des HHV-6A et HHV-6B est transmissible de façon héréditaire et concerne environ 1 % de la population générale. Elle pose la question des éventuelles maladies associées et peut être un facteur de confusion pour le diagnostic des infections actives par ces deux virus. Le diagnostic des infections à HHV-6A, HHV-6B et HHV-7 se fonde plus sur la PCR, qui permet la détection et la quantification du génome viral, que sur la sérologie, indiquée essentiellement en cas de primo-infection. Le ganciclovir, le foscarnet et le cidofovir inhibent la réplication de ces virus, ce qui permet le traitement des infections graves. Les indications ne sont cependant pas encore bien codifiées.
Published: 2016

34. Intraocular pressure reduction and neuroprotection conferred by bone marrow-derived mesenchymal stem cells in an animal model of glaucoma

Author: William Rostène, David Godefroy, José-Alain Sahel, Anaïs Sapienza, Luisa Riancho, Christophe Baudouin, Françoise Brignole-Baudouin, Ivana Ivkovic, Alexandre Denoyer, Julie Degardin, Céline Mias, Valérie Fradot, Serge Picaud, Florian Sennlaub, Stéphane Melik Parsadaniantz, Christophe Roubeix, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physiopathologie Cellulaire et Moleculaire de la Retine, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement, vieillissement et pathologie de la rétine, Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie cellulaire des neurorécepteurs et physiopathologie neuroendocrinienne, Université Sorbonne Paris Cité (USPC), Physiopathologie des Maladies Oculaires : Innovations Therapeutiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), HAL-UPMC, Gestionnaire, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Hôpital des Quinze-Vingts, Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Hôpital Ambroise Paré, and Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ )
Subjects: Male, medicine.medical_specialty, Intraocular pressure, Pathology, genetic structures, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Ocular hypertension, Glaucoma, Apoptosis, Mesenchymal Stem Cell Transplantation, Biochemistry, Genetics and Molecular Biology (miscellaneous), [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Animals, Rats, Long-Evans, Cells, Cultured, Intraocular Pressure, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Research, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, medicine.disease, eye diseases, Rats, 3. Good health, Surgery, Transplantation, medicine.anatomical_structure, Molecular Medicine, Trabecular meshwork, Bone marrow, sense organs, Stem cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Introduction Glaucoma is a sight-threatening retinal neuropathy associated with elevated intraocular pressure (IOP) due to degeneration and fibrosis of the trabecular meshwork (TM). Glaucoma medications aim to reduce IOP without targeting the specific TM pathology, Bone-marrow mesenchymal stem cells (MSCs) are used today in various clinical studies. Here, we investigated the potential of MSCs therapy in an glaucoma-like ocular hypertension (OHT) model and decipher in vitro the effects of MSCs on primary human trabecular meshwork cells. Methods Ocular hypertension model was performed by cauterization of 3 episcleral veins (EVC) of Long-Evans male rat eyes. MSCs were isolated from rat bone marrow, amplified in vitro and tagged with quantum dot nanocrystals. Animals were distributed as 1) MSCs group receiving 5.105cells/6μl Minimum Essential Medium and 2) MEM group receiving 6μl MEM (n = 10 each). Injections were performed into the anterior chamber of 20 days-hypertensive eyes and IOP was monitored twice a week for 4 weeks. At the end of experiment, cell distribution in the anterior segment was examined in confocal microscopy on flat mounted corneas. Moreover, we tested in vitro effects of MSCs conditioned medium (MSC-CM) on primary human trabecular meshwork cells (hTM cells) using Akt activation, myosin phosphorylation and TGF-β2-dependent profibrotic phenotype in hTM cells. Results We demonstrated a rapid and long-lasting in vivo effect of MSCs transplantation that significantly reduced IOP in hypertensive eyes induced by EVC. MSCs were located to the ciliary processes and the TM. Enumeration of RGCs on whole flat-mounted retina highlighted a protective effect of MSCs on RGCs death. In vitro, MSC-CM promotes: (i) hTM cells survival by activating the antiapoptotic pathway, Akt, (ii) hTM cells relaxation as analyzed by the decrease in myosin phosphorylation and (iii) inhibition of TGF-β2-dependent profibrotic phenotype acquisition in hTM cells. Conclusions MSCs injection in the ocular anterior chamber in a rat model of OHT provides neuroprotective effect in the glaucoma pathophysiology via TM protection. These results demonstrate that MSCs constitute promising tool for treating ocular hypertension and retinal cell degeneration.
Published: 2015

35. Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology

Author: Kristin Michaelsen-Preusse, Sophie Ayciriex, David Blum, Luc Buée, Marie-Claude Potier, Ivan Bièche, Francisco-Jose Fernandez-Gomez, Fathia Djelti, Luce Dauphinot, Jérôme Braudeau, Raphaëlle Caillierez, Nathalie Cartier, Marie-Anne Burlot, Olivier Laprévote, Benoit Gautier, Patrick Dutar, Martin Korte, Mickael Audrain, Brigitte Potier, Nicolas Auzeil, Jennifer Varin, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Zoological Institute, Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig], Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Inserm U986, Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes adaptatifs : des organismes aux communautés, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Alzheimer & Tauopathies [JPArc], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Facultés des sciences pharmaceutiques et biologiques, Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Thérapie génique, Génomique et Epigénomique ( U 1169 ), Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Technische Universität Braunschweig [Braunschweig], Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux ( EA 7331 ), Institut National de la Santé et de la Recherche Médicale, Mécanismes adaptatifs : des organismes aux communautés ( MECADEV ), Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ), Alzheimer & Tauopathies ( Equipe 1 ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172 ( JPArc ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Department of Cellular and Systems Neurobiology, Max-Planck-Institut für Neurobiologie, Service MIRCEN ( MIRCEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Alzheimer & Tauopathies (Equipe 1), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Saclay-Institut de Biologie François JACOB (JACOB)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Mice, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Gliosis, Phosphorylation, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, medicine.anatomical_structure, Tauopathies, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Alzheimer's disease, medicine.symptom, medicine.medical_specialty, Amyloid, Central nervous system, Mice, Transgenic, tau Proteins, Biology, 03 medical and health sciences, Alzheimer Disease, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cholesterol 24-Hydroxylase, Genetics, medicine, Animals, Humans, Cholesterol 24-hydroxylase, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, 030304 developmental biology, Memory Disorders, Cholesterol, medicine.disease, Hydroxycholesterols, Disease Models, Animal, Endocrinology, chemistry, Steroid Hydroxylases, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, 030217 neurology & neurosurgery, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: Alzheimer's disease (AD) is characterized by both amyloid and Tau pathologies. The amyloid component and altered cholesterol metabolism are closely linked, but the relationship between Tau pathology and cholesterol is currently unclear. Brain cholesterol is synthesized in situ and cannot cross the blood-brain barrier: to be exported from the central nervous system into the blood circuit, excess cholesterol must be converted to 24S-hydroxycholesterol by the cholesterol 24-hydroxylase encoded by the CYP46A1 gene. In AD patients, the concentration of 24S-hydroxycholesterol in the plasma and the cerebrospinal fluid are lower than in healthy controls. The THY-Tau22 mouse is a model of AD-like Tau pathology without amyloid pathology. We used this model to investigate the potential association between Tau pathology and CYP46A1 modulation. The amounts of CYP46A1 and 24S-hydroxycholesterol in the hippocampus were lower in THY-Tau22 than control mice. We used an adeno-associated virus (AAV) gene transfer strategy to increase CYP46A1 expression in order to investigate the consequences on THY-Tau22 mouse phenotype. Injection of the AAV-CYP46A1 vector into the hippocampus of THY-Tau22 mice led to CYP46A1 and 24S-hydroxycholesterol content normalization. The cognitive deficits, impaired long-term depression and spine defects that characterize the THY-Tau22 model were completely rescued, whereas Tau hyperphosphorylation and associated gliosis were unaffected. These results argue for a causal link between CYP46A1 protein content and memory impairments that result from Tau pathology. Therefore, CYP46A1 may be a relevant therapeutic target for Tauopathies and especially for AD.
Published: 2015

36. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease

Author: Dominique Langui, Michel Vidaud, Eloise Hudry, Nathalie Cartier, Ivan Bièche, Marc Dhenain, Sandro Alves, Olivier Laprévote, Patrick Aubourg, Sophie Ayciriex, Charles Duyckaerts, Jérôme Braudeau, Catherine Marquer, Nicolas Auzeil, Farah Chali, Marie-Claude Potier, Richard B. Miles, Fathia Djelti, Jennifer Varin, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Mécanismes adaptatifs : des organismes aux communautés, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Facultés des sciences pharmaceutiques et biologiques, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Inserm U986, Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Mécanismes adaptatifs : des organismes aux communautés ( MECADEV ), Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ), Thérapie génique, Génomique et Epigénomique ( U 1169 ), Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Laboratoire des Maladies Neurodégénératives - UMR 9199 ( LMN ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux ( EA 7331 ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale, Service MIRCEN ( MIRCEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Hippocampal formation, Small hairpin RNA, chemistry.chemical_compound, Amyloid beta-Protein Precursor, 0302 clinical medicine, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], RNA interference, Homeostasis, Enzyme Inhibitors, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Lipid raft, ComputingMilieux_MISCELLANEOUS, Neurons, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Neurodegeneration, Brain, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Cholesterol, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Female, medicine.medical_specialty, Mice, Transgenic, Biology, 03 medical and health sciences, Alzheimer Disease, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Cholesterol 24-Hydroxylase, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Liver X receptor, 030304 developmental biology, Amyloid beta-Peptides, medicine.disease, Mice, Inbred C57BL, Endocrinology, chemistry, Steroid Hydroxylases, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of β-C-terminal fragment and amyloid-β peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-β peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease.
Published: 2015

37. Factors associated with non-persistence to oral and inhaled antiviral therapies for seasonal influenza: a secondary analysis of a double-blind, multicentre, randomised clinical trial

Author: Rémi Flicoteaux, Anne Mosnier, Xavier Duval, Sylvie Chevret, Sylvie van der Werf, Camelia Protopopescu, Catherine Leport, Thierry Blanchon, Cécile Charlois-Ou, Bruno Lina, Annick Tibi, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut national du cancer [Boulogne] (INCA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de Référence de la Grippe (France Nord) - Centre Collaborateur de l'OMS Grippe et autres virus respiratoires (CNR - CCOMS), Institut Pasteur [Paris], Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Réseau des Groupes Régionaux d'Observation de la Grippe (GROG), Coordination nationale, Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR), Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de biostatistiques et information médicale [Saint-Louis], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), French Ministry of Health, Département à la Recherche Clinique et au Développement, Assistance Publique Hôpitaux de Paris (Programme hospitalier de recherche clinique, AOM 06060 et AOM 08209), Lissalde, Claire, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR - laboratoire associé), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: Male, Antibiotics, Administration, Oral, Kaplan-Meier Estimate, 01 natural sciences, 010104 statistics & probability, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Clinical endpoint, Medicine, Zanamivir, 030212 general & internal medicine, General Medicine, 3. Good health, Treatment Outcome, Infectious Diseases, Medication Non-Adherence, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, medicine.drug, medicine.medical_specialty, Oseltamivir, medicine.drug_class, Randomized, Controlled Clinical Trials, Placebo, Antiviral Agents, Medication Adherence, 03 medical and health sciences, Route of administration, Double-Blind Method, Internal medicine, Administration, Inhalation, Influenza, Human, Humans, 0101 mathematics, Medical prescription, Proportional Hazards Models, business.industry, Research, Human Influenza, Surgery, Clinical trial, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Multivariate Analysis, Lost to Follow-Up, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Objectives We aimed to evaluate and compare non-adherence to oral and inhaled antiviral therapies prescribed of a randomised clinical trial in outpatients with influenza A infection. Design A parallel, three-arm, double-blinded trial randomly allocated antiviral therapies twice daily for 5 days: (1) oral oseltamivir plus inhaled zanamivir (arm OZ); (2) oseltamivir plus inhaled placebo (arm Opz); or (3) oral placebo plus inhaled zanamivir (arm poZ). Analysis of non-adherence was a secondary objective of the trial. Settings Outpatients were enrolled by 145 general practitioners throughout France during the 2008–2009 seasonal influenza epidemics. Participants A total of 541 adults presenting with influenza-like illness for less than 36 hours. Primary outcomes Non-persistence, the time between inclusion and the last dose treated as a failure time, was used as the primary endpoint. Results The proportions of patients who persisted on treatment until the end of prescription were estimated at 85.73% (±3.28%) for the oral route and 82.73% (±3.44%) for the inhaled route. Based on multivariable models, non-persistence was associated with a PCR confirmation of influenza for both the oral (HR=0.54, p=0.010) and inhaled (HR=0.59, p=0.018) drugs and antibiotic coprescriptions (HR=2.07, p=0.007; and HR=1.88, p=0.017, respectively) and active combination treatment (HR=1.71, p=0.035; and HR=1.58, p=0.035, respectively). The hazard of non-persistence of the inhaled therapy was increased compared with that of the oral therapy (HR=1.23, p=0.043). Conclusion In addition to the clinical and virological profiles of influenza infection, non-persistence may have been influenced by an active combination and the route of administration. RCT registration number NCT00799760. This is a post-result analysis.
Published: 2017

38. Ultra performance liquid chromatography - mass spectrometry studies of formalin-induced alterations of human brain lipidome

Author: Ayciriex , Sophie, Gaudin , Mathieu, Panchal , Mai, Werner , Erwan, Brunelle , Alain, Touboul , David, Boursier-Neyret , Claire, Auzeil , Nicolas, Walther , Bernard, Duyckaerts , Charles, Laprévote , Olivier, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Géosciences Marines (GM), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Unité de recherche Géosciences Marines (Ifremer) (GM), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon, Unité de recherche Géosciences Marines (Ifremer) ( GM ), Institut Français de Recherche pour l'Exploitation de la Mer ( IFREMER ), ICNS - Institut de Chimie des Substances naturelles, Laboratoire d'Etude du Métabolisme des Médicaments ( LEMM ), Service de Pharmacologie et Immunoanalyse ( SPI ), Département Médicaments et Technologies pour la Santé ( DMTS ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Département Médicaments et Technologies pour la Santé ( DMTS ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [CHIM.ORGA]Chemical Sciences/Organic chemistry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: International audience
Published: 2014

39. Dynamics in the Cytoadherence Phenotypes of Plasmodium falciparum Infected Erythrocytes Isolated during Pregnancy

Author: Nicaise Tuikue Ndam, Achille Massougbodji, Sylvain Sossou-tchatcha, Philippe Deloron, Gilles Cottrell, Justin Doritchamou, Christophe Hounton Houngbeme, Azizath Moussiliou, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Université d’Abomey-Calavi = University of Abomey Calavi (UAC), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Physiologie, physiopathologie et thérapeutique (ED 394), Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital de zone Suru Léré, Cotonou, Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), University of Abomey Calavi (UAC), Mère et enfant face aux infections tropicales ( MERIT - UMR_D 216 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut de Recherche pour le Développement ( IRD ), University of Abomey Calavi ( UAC ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Physiologie, physiopathologie et thérapeutique ( ED 394 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: CD36 Antigens, Erythrocytes, Time Factors, Transcription, Genetic, Placenta, Protozoan Proteins, lcsh:Medicine, Cell Separation, 0302 clinical medicine, Pregnancy, Medicine and Health Sciences, lcsh:Science, 0303 health sciences, Multidisciplinary, biology, Chondroitin Sulfates, Pregnancy Outcome, Intercellular Adhesion Molecule-1, Acquired immune system, 3. Good health, Parity, Infectious Diseases, Phenotype, medicine.anatomical_structure, Female, Research Article, Adult, Immunology, Plasmodium falciparum, 030231 tropical medicine, Antigens, Protozoan, Gestational Age, Receptors, Cell Surface, Young Adult, 03 medical and health sciences, Antigen, Immunity, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, parasitic diseases, Cell Adhesion, medicine, Humans, Cell adhesion, Molecular Biology, 030304 developmental biology, lcsh:R, Biology and Life Sciences, Cell Biology, Tropical Diseases, medicine.disease, biology.organism_classification, Virology, Gene Expression Regulation, Women's Health, Parasitology, lcsh:Q, Malaria, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Pregnant women become susceptible to malaria infection despite their acquired immunity to this disease from childhood. The placental sequestration of Plasmodium falciparum infected erythrocytes (IE) is the major feature of malaria during pregnancy, due to ability of these parasites to bind chondroitin sulfate A (CSA) in the placenta through the VAR2CSA protein that parasites express on the surface of IE. We collected parasites at different times of pregnancy and investigated the adhesion pattern of freshly collected isolates on the three well described host receptors (CSPG, CD36 and ICAM-1). Var genes transcription profile and VAR2CSA surface-expression were assessed in these isolates. Although adhesion of IE to CD36 and ICAM-1 was observed in some isolates, CSA-adhesion was the predominant binding feature in all isolates analyzed. Coexistence in the peripheral blood of several adhesion phenotypes in early pregnancy isolates was observed, a diversity that gradually tightens with gestational age in favour of the CSA-adhesion phenotype. Infections occurring in primigravidae were often by parasites that adhered more to CSA than those from multigravidae. Data from this study further emphasize the specificity of CSA adhesion and VAR2CSA expression by parasites responsible for pregnancy malaria, while drawing attention to the phenotypic complexity of infections occurring early in pregnancy as well as in multigravidae.
Published: 2014

40. Evaluation of the effectiveness of malaria vector control measures in urban settings of Dakar by a specific anopheles salivary biomarker

Author: Olayidé Boussari, Richard Lalou, Stéphanie Dos Santos, Vanessa Machault, Sylvie Cornelie, Papa M. Drame, Abdoulaye Diallo, Jean-Yves LeHesran, Anne Poinsignon, Franck Remoue, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle ( MIVEGEC ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD [France-Sud] ), Santé de la mère et de l'enfant en milieu tropical : épidémiologie génétique et périnatale, Université Paris Descartes - Paris 5 ( UPD5 ), Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire Population-Environnement-Développement ( LPED ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ), Laboratoire d'aérologie - LA ( LA ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire Midi-Pyrénées ( OMP ) -Centre National de la Recherche Scientifique ( CNRS ), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Transmission-Interactions-Adaptations hôtes/vecteurs/pathogènes (MIVEGEC-TRIAD), Evolution des Systèmes Vectoriels (ESV), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Université d’Abomey-Calavi = University of Abomey Calavi (UAC), Laboratoire Population-Environnement-Développement (LPED), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), Laboratoire d'aérologie (LAERO), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Vector Control Group (MIVEGEC-VCG), ANR-07-SEST-0001,ACTU-PALU,Paludisme et diversité de l'environnement urbain africain : un enjeu majeur pour la mise en place des ACT(2007), University of Abomey Calavi (UAC), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), Laboratoire d'aérologie (LA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), and ANR n°2007 SEST 001 02,SEST 001 02, ANR n°2007 SEST 001 02
Subjects: Male, Insecticides, Mosquito Control, Urban Population, Epidemiology, lcsh:Medicine, Global Health, Mosquitoes, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Salivary biomarkers, lcsh:Science, Urban areas, Child, Immune Response, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, biology, Anopheles, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Senegal, Socioeconomic Aspects of Health, 3. Good health, Mosquito control, Infectious Diseases, Child, Preschool, Biomarker (medicine), Insect Proteins, Medicine, Female, Public Health, Research Article, Adult, Adolescent, Infectious Disease Control, 030231 tropical medicine, Immunology, Malaria vector control, Immunoglobulins, Insect bites and stings, 03 medical and health sciences, Environmental health, parasitic diseases, medicine, Parasitic Diseases, Animals, Humans, Insecticide-Treated Bednets, Salivary Proteins and Peptides, Biology, 030304 developmental biology, lcsh:R, Immunity, Insect Bites and Stings, Vectors and Hosts, biology.organism_classification, medicine.disease, Insect Vectors, Malaria, Vector (epidemiology), Immunoglobulin G, Insect Repellents, Africa, Immunologic Techniques, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Preventive Medicine, Infectious Disease Modeling, Biomarkers
Abstract: International audience; Standard entomological methods for evaluating the impact of vector control lack sensitivity in low-malaria-risk areas. The detection of human IgG specific to Anopheles gSG6-P1 salivary antigen reflects a direct measure of human-vector contact. This study aimed to assess the effectiveness of a range of vector control measures (VCMs) in urban settings by using this biomarker approach. The study was conducted from October to December 2008 on 2,774 residents of 45 districts of urban Dakar. IgG responses to gSG6-P1 and the use of malaria VCMs highly varied between districts. At the district level, specific IgG levels significantly increased with age and decreased with season and with VCM use. The use of insecticide-treated nets, by drastically reducing specific IgG levels, was by far the most efficient VCM regardless of age, season or exposure level to mosquito bites. The use of spray bombs was also associated with a significant reduction of specific IgG levels, whereas the use of mosquito coils or electric fans/air conditioning did not show a significant effect. Human IgG response to gSG6-P1 as biomarker of vector exposure represents a reliable alternative for accurately assessing the effectiveness of malaria VCM in low-malaria-risk areas. This biomarker tool could be especially relevant for malaria control monitoring and surveillance programmes in low-exposure/low-transmission settings.
Published: 2012

41. In Vivo Visualization of Delta Opioid Receptors upon Physiological Activation Uncovers a Distinct Internalization Profile

Author: Yannick Schwab, Jean-Luc Vonesch, Julie Le Merrer, Brigitte L. Kieffer, Audrey Matifas, Marion Decossas, Nadia Benturquia, Lauren Faget, Eric Erbs, Pascal Kessler, Florence Noble, Dominique Massotte, Grégory Scherrer, Marc Koch, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Astrophysique de Marseille (LAM), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique (NAVVEC - UM 81 (UMR 8206/ U705)), Université Paris Diderot - Paris 7 (UPD7)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Géographie Physique et Environnementale (GEOLAB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut Sciences de l'Homme et de la Société (IR SHS UNILIM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), and Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie)
Subjects: Male, Agonist, medicine.drug_class, Enkephalin, Methionine, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Context (language use), Stimulation, Biology, Pharmacology, Hippocampus, Article, Mice, In vivo, Receptors, Opioid, delta, medicine, Animals, Gene Knock-In Techniques, Receptor, Opioid peptide, Internalization, G protein-coupled receptor, media_common, Morphine, General Neuroscience, Molecular Imaging, Substance Withdrawal Syndrome, Cell biology, Mice, Inbred C57BL, Protein Transport, Female
Abstract: G-protein-coupled receptors (GPCRs) mediate numerous physiological functions and represent prime therapeutic targets. Receptor trafficking upon agonist stimulation is critical for GPCR function, but examining this processin vivoremains a true challenge. Using knock-in mice expressing functional fluorescent delta opioid receptors under the control of the endogenous promoter, we visualizedin vivointernalization of this native GPCR upon physiological stimulation. We developed a paradigm in which animals were made dependent on morphine in a drug-paired context. When re-exposed to this context in a drug-free state, mice showed context-dependent withdrawal signs and activation of the hippocampus. Receptor internalization was transiently detected in a subset of CA1 neurons, uncovering regionally restricted opioid peptide release. Importantly, a pool of surface receptors always remained, which contrasts with thein vivoprofile previously established for exogenous drug-induced internalization. Therefore, a distinct response is observed at the receptor level upon a physiological or pharmacological stimulation. Altogether, directin vivoGPCR visualization enables mapping receptor stimulation promoted by a behavioral challenge and represents a powerful approach to study endogenous GPCR physiology.
Published: 2012

42. Defects in Gallbladder Emptying and Bile Acid Homeostasis in Mice With Cystic Fibrosis Transmembrane Conductance Regulator Deficiencies

Author: Chantal Housset, Paul A. Dawson, Colette Rey, Dominique Debray, Charles Henry Cottart, Dominique Rainteau, Lydie Humbert, Dominique Wendum, Myriam Rouahi, Haquima El Mourabit, Véronique Barbu, Stéphanie Lerondel, Nicolas Chignard, Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), Laboratoire de mécanique des sols, structures et matériaux (MSSMat), CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Transgénèse et Archivage d'Animaux Modèles - Centre d'Imagerie du Petit Animal ( TAAM-CIPA ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de mécanique des sols, structures et matériaux ( MSSMat ), CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Transgénèse et Archivage d'Animaux Modèles - Centre d'Imagerie du Petit Animal (TAAM-CIPA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Gallbladder Emptying, Cystic Fibrosis, medicine.drug_class, Vasoactive intestinal peptide, education, Cystic Fibrosis Transmembrane Conductance Regulator, Biology, Cystic fibrosis, Bile Acids and Salts, Mice, 03 medical and health sciences, 0302 clinical medicine, [ CHIM.ORGA ] Chemical Sciences/Organic chemistry, Internal medicine, medicine, Animals, Bile, Homeostasis, Cholecystectomy, ΔF508, Enterohepatic circulation, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Hepatology, Bile acid, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Gallbladder, Gastroenterology, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Mice, Inbred C57BL, medicine.anatomical_structure, Endocrinology, biology.protein, 030211 gastroenterology & hepatology
Abstract: Background & Aims Patients with cystic fibrosis (CF) have poorly defined defects in biliary function. We evaluated the effects of cystic fibrosis transmembrane conductance regulator (CFTR) deficiency on the enterohepatic disposition of bile acids (BAs). Methods Bile secretion and BA homeostasis were investigated in Cftr tm1Unc ( Cftr −/− ) and CftrΔF508 (ΔF508) mice. Results Cftr −/− and ΔF508 mice did not grow to normal size, but did not have liver abnormalities. The gallbladders of Cftr −/− mice were enlarged and had defects in emptying, based on 99m technetium-mebrofenin scintigraphy or post-prandial variations in gallbladder volume; gallbladder contraction in response to cholecystokinin-8 was normal. Cftr −/− mice had abnormal gallbladder bile and duodenal acidity, and overexpressed the vasoactive intestinal peptide—a myorelaxant factor for the gallbladder. The BA pool was larger in Cftr −/− than wild-type mice, although there were no differences in fecal loss of BAs. Amounts of secondary BAs in portal blood, liver, and bile of Cftr −/− mice were much lower than normal. Expression of genes that are induced by BAs, including fibroblast growth factor-15 and BA transporters, was lower in the ileum but higher in the gallbladders of Cftr −/− mice, compared with wild-type mice, whereas enzymes that synthesize BA were down-regulated in livers of Cftr −/− mice. This indicates that BAs underwent a cholecystohepatic shunt, which was confirmed using cholyl-(Ne-NBD)-lysine as a tracer. In Cftr −/− mice, cholecystectomy reversed most changes in gene expression and partially restored circulating levels of secondary BAs. The ΔF508 mice overexpressed vasoactive intestinal peptide and had defects in gallbladder emptying and in levels of secondary BAs, but these features were less severe than in Cftr −/− mice. Conclusions Cftr −/− and CftrΔF508 mice have defects in gallbladder emptying that disrupt enterohepatic circulation of BAs. These defects create a shunt pathway that restricts the amount of toxic secondary BAs that enter the liver.
Published: 2012

43. CXCR3 antagonism of SDF-1(5-67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension

Author: William Rostène, Julie Frugier, Françoise Baleux, David Godefroy, Isabelle Célérier, Serge Picaud, Françoise Brignole-Baudouin, Julie Degardin, Jeffrey K. Harrison, Christophe Baudouin, José Sahel, Alexandre Denoyer, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche des Cordeliers - Equipe 20 'ingénierie des connaissances en santé', Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Florida [Gainesville] (UF), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Chimie des biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), CIC Quinze-Vingts, Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Laboratory of Toxicology, Faculty of Pharmaceutical and Biological Sciences, Université Paris Descartes - Paris 5 ( UPD5 ), Chimie des Biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), This work was supported by INSERM grants for AD, DG, JD, WR and CB, by a UPMC grant for IC and JF, and by an NIH grant for JKH (AI058256)., Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) ( APHP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Godefroy, David
Subjects: Retinal degeneration, Male, Visual System, Ocular hypertension, Apoptosis, MESH : Cytoprotection, MESH : Receptors, CXCR4, MESH : Receptors, CXCR3, 0302 clinical medicine, MESH: Animals, lcsh:Science, MESH: Stress, Physiological, MESH : Glaucoma, 0303 health sciences, Neurodegeneration, Anatomy, MESH : Chemokine CXCL12, Sensory Systems, 3. Good health, [SDV] Life Sciences [q-bio], MESH : Retinal Degeneration, Medicine, MESH: Chemokine CXCL12, MESH: Glaucoma, medicine.medical_specialty, MESH: Enzyme Activation, Receptors, CXCR4, Receptors, CXCR3, MESH: Retinal Degeneration, Ocular Anatomy, Caspase 3, MESH: Receptors, CXCR4, MESH: Receptors, CXCR3, 03 medical and health sciences, Humans, Rats, Long-Evans, MESH: Vision, Ocular, Biology, Intraocular Pressure, MESH: Humans, [ SDV ] Life Sciences [q-bio], lcsh:R, MESH : Humans, Glaucoma, medicine.disease, MESH : Disease Models, Animal, eye diseases, Chemokine CXCL12, MESH: Cell Line, MESH: Ocular Hypertension, Enzyme Activation, MESH: Cytoprotection, Ophthalmology, Endocrinology, chemistry, 030221 ophthalmology & optometry, Rat, lcsh:Q, Ocular Hypertension, Trabecular meshwork, MESH: Disease Models, Animal, MESH : Apoptosis, Neuroscience, MESH : Cell Line, Intraocular pressure, Anatomy and Physiology, genetic structures, [SDV]Life Sciences [q-bio], MESH : Vision, Ocular, lcsh:Medicine, chemistry.chemical_compound, MESH: Caspase 3, Molecular Cell Biology, MESH : Caspase 3, MESH : Rats, Long-Evans, MESH : Intraocular Pressure, Multidisciplinary, Cell Death, MESH : Rats, Retinal Degeneration, Animal Models, MESH : Trabecular Meshwork, medicine.anatomical_structure, Research Article, MESH: Rats, MESH : Male, Cell Line, Model Organisms, MESH: Intraocular Pressure, MESH: Rats, Long-Evans, Stress, Physiological, Trabecular Meshwork, Ocular System, Internal medicine, medicine, MESH : Ocular Hypertension, Animals, MESH : Stress, Physiological, Vision, Ocular, 030304 developmental biology, MESH: Apoptosis, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Retinal, MESH: Male, Rats, MESH: Trabecular Meshwork, Disease Models, Animal, Cytoprotection, MESH : Animals, sense organs, MESH : Enzyme Activation
Abstract: International audience; Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.
Published: 2012

44. Congenital tracheal malformation in cystic fibrosis transmembrane conductance regulator-deficient mice

Author: Bonvin, Elise, Le Rouzic, Philippe, Bernaudin, Jean-François, Cottart, Charles-Henry, Vandebrouck, Clarisse, Crie, Antoine, Leal, Teresinha, Clément, Annick, Bonora, Monique, Physiologie, biologie des organismes, populations, interactions, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Institut de physiologie et biologie cellulaires (IPBC), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Catholique de Louvain = Catholic University of Louvain (UCL), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL - MD/BICL - Département de biochimie et de biologie cellulaire, UCL - (SLuc) Service de biochimie médicale, Laboratoire d'Histologie-Biologie tumorale, Université Catholique de Louvain (UCL), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de physiologie et biologie cellulaires ( IPBC ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Université Catholique de Louvain ( UCL ), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: Mice, Knockout, congenital, hereditary, and neonatal diseases and abnormalities, Tracheal Diseases, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Respiration, Cystic Fibrosis Transmembrane Conductance Regulator, Muscle, Smooth, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, respiratory system, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, digestive system diseases, respiratory tract diseases, Trachea, Mice, Respiratory, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, [ SDV.MHEP.PSR ] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Muscle Contraction
Abstract: (IF : 4,58); International audience; In cystic fibrosis (CF) patients, the major alteration in pulmonary function is due to peripheral airway obstruction. In the present study, we investigated the possibility that alterations in the extrathoracic airways, particularly in the trachea that expresses high levels of CFTR (CF transmembrane conductance regulator), may contribute to respiratory dysfunction. We performed morphological analyses of the trachea and airway functional studies in adult Cftr knockout (Cftr−/−) and F508del-CFTR mice and their controls. Macroscopic and histological examination of the trachea showed the presence of one to seven disrupted or incomplete cartilage rings in Cftr−/− mice (23/25) while only a few Cftr+/+ mice (6/25) had one abnormal ring. Tracheal defects were mainly localized in the proximal trachea. In 14 Cftr−/− mice, frontal disruption of the first three to six rings below the cricoid cartilage were associated with upper tracheal constriction. Similar tracheal abnormalities were detected in adult F508del-CFTR and in newborn Cftr−/− and F508del-CFTR mice. Tracheal and ventilatory function analyses showed in Cftr−/− mice a decreased contractile response of the proximal trachea and a reduced breathing rate due to an increase in the inspiratory and expiratory times. In F508del-CFTR mice, the expiratory time was longer than in controls. Therefore, these structural and functional abnormalities detected in adult and newborn CF mouse models may represent congenital malformations related toCFTRdysfunction. These results raise important questions concerning themechanismsgoverning trachealdevelopmentwithin the context ofCFTRproteindysfunction and the implication of such abnormalities in the pathogenesis of airway disease in CF
Published: 2008

45. Neuropilin 1 and CD25 co-regulation during early murine thymic differentiation

Author: Colette Agboton, Anne-Sophie Pelus, C Corbel, Paul-Henri Romeo, Véronique Thomas-Vaslin, Valérie Lemarchandel, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie et thérapeutique des pathologies immunitaires (BTPI), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche sur la Réparation et la Transcription dans les Cellules Souches (LRTS), Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Immunologie - Immunopathologie - Immunothérapie (I3), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Vascular Endothelial Growth Factor A, CD3, T cell, Immunology, Mice, Transgenic, Thymus Gland, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, T-Lymphocyte Subsets, Neuropilin 1, medicine, Animals, IL-2 receptor, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Lymphopoiesis, Interleukin-2 Receptor alpha Subunit, FOXP3, Cell Differentiation, Dendritic cell, Dendritic Cells, Molecular biology, Neuropilin-1, Mice, Inbred C57BL, Thymocyte, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, biology.protein, Female, 030217 neurology & neurosurgery, CD8, Developmental Biology
Abstract: Neuropilin 1 (NP1) is a receptor for both semaphorin and vascular endothelial growth factor expressed by subpopulations of neuronal and endothelial cells. In the immune system, NP1 is present on dendritic and regulatory T cells. Here, we show that NP1 is expressed in the murine thymus, starting on day 12.5 of gestation. In the adult, NP1 is mainly expressed by CD4 − CD8 − double negative cells, CD4 + CD8 + double positive cells, and CD4 + CD25 + regulatory T cells but barely detected in single CD4 + and CD8 + positive thymocytes. Within the CD4 − CD8 − CD3 − (triple-negative, TN) immature cells, NP1 expression starts in TN3 (CD44 − CD25 + ) and increases in TN4 (CD44 − CD25 − ) cells. In order to study the role of NP1 in thymocyte differentiation, we generated mice in which the np1 gene is selectively disrupted in the T-cell lineage. The mutant mice display normal thymocyte, peripheral, conventional and CD4 + CD25 + Foxp3 + regulatory T-cell populations. However, we observe a down-regulation of the CD25 expression between the TN3 and TN4 stages that is (i) correlated to increased expression of NP1 in control mice and (ii) altered in mutant mice, suggesting that NP1 is co-regulated with CD25 during early immature thymocyte differentiation.
Published: 2006

46. Determination of Morphological, Biometric and Biochemical Susceptibilities in Healthy Eurasier Dogs with Suspected Inherited Glaucoma

Author: Nicolas Froger, Nathalie Neveux, Thomas Boillot, Serge Picaud, Ivana Ivkovic, Philippe Thomas, Stéphanie Lafarge-Beurlet, Thomas Dulaurent, Sylvie Lavillegrand, Pierre François Isard, José-Alain Sahel, Frédéric Goulle, Mike Woods, Thierry Azoulay, Serge G. Rosolen, Clinique vétérinaire Vetea, Saintes, Clinique Vétérinaire Voltaire, Institut de la Vision, Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre hospitalier vétérinaire Saint Martin de Bellevue, Clinique vétérinaire Aviquet, Eysines, Clinique vétérinaire Saint Pierre, Saint-Chamond, Clinique vétérinaire des Halles, Strasbourg, Vébio, Arcueil, Pimrose Hill Veterinary Clinic, Dublin, Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), CHU Cochin [AP-HP], Fondation Ophtalmologique Adolphe de Rotschild, CIC Quinze-Vingts, Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, University College of London [London] ( UCL ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), University College of London [London] (UCL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and HAL UPMC, Gestionnaire
Subjects: Male, Intraocular pressure, Pathology, Eye Diseases, genetic structures, Visual System, Ultrasound biomicroscopy, lcsh:Medicine, Glaucoma, Cohort Studies, 0403 veterinary science, 0302 clinical medicine, Medicine and Health Sciences, Medicine, lcsh:Science, 10. No inequality, Ultrasonography, Multidisciplinary, medicine.diagnostic_test, 04 agricultural and veterinary sciences, Sensory Systems, Health, Cohort, Female, Disease Susceptibility, Anatomy, Research Article, Cohort study, medicine.medical_specialty, Biometry, Manometry, 040301 veterinary sciences, Gonioscopy, Ophthalmoscopy, 03 medical and health sciences, Dogs, Ocular System, Ophthalmology, Animals, Risk factor, Intraocular Pressure, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, business.industry, lcsh:R, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Biology and Life Sciences, medicine.disease, eye diseases, 030221 ophthalmology & optometry, lcsh:Q, [ SDV.BA.MVSA ] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, business, Neuroscience
Abstract: International audience; In both humans and dogs, the primary risk factor for glaucoma is high intraocular pressure (IOP), which may be caused by iridocorneal angle (ICA) abnormalities. Oxidative stress has also been implicated in retinal ganglion cell damage associated with glaucoma. A suspected inherited form of glaucoma was recently identified in Eurasier dogs (EDs), a breed for which pedigrees are readily available. Because of difficulties in assessing ICA morphology in dogs with advanced glaucoma, we selected a cohort of apparently healthy dogsfor the investigation of ICA morphological status, IOP and plasma concentrations of oxidative stress biomarkers. We aimed to establish correlations between these factors, to identify predictive markers of glaucoma in this dog breed. A cohort of 28 subjects, volunteered for inclusion by their owners, was selected by veterinary surgeons. These dogs were assigned to four groups: young males, young females (1–3 years old), adult males and adult females (4–8 years old). Ocular examination included ophthalmoscopy, tonometry, gonioscopy, biometry and ultrasound biomicroscopy (UBM), and the evaluation of oxidative stress biomarkers consisting of measurements of plasma glutathione peroxidase (GP) activity and taurine and metabolic precursor (methionine and cysteine) concentrations in plasma. The prevalence of pectinate ligament abnormalities was significantly higher in adult EDs than in young dogs. Moreover, in adult females, high IOP was significantly correlated with a short axial globe length, and a particularly large distance between Schwalbe's line and the anterior lens capsule. GP activity levels were significantly lower in EDs than in a randomized control group of dogs, and plasma taurine concentrations were higher. Hence, ICA abnormalities were associated with weaker antioxidant defenses in EDs, potentially counteracted by higher plasma taurine concentrations. This study suggests that EDs may constitute an appropriate canine model for the development of glaucoma. This cohort will be used as a sentinel for longitudinal monitoring.
Published: 2014

47. Etude de l'histamine au cours du développement des lesions consecutives à une ischémie cérébrale néonatale

Author: Héron, Anne, Cochois, Véronique, Biran, Valérie, Arrang, Jean-Michel, Charriaut-Marlangue, Christiane, Unité de Recherche Clinique et d'Evaluation Scientifique URC28 (URC28), Centre Hospitalier Victor Jousselin de Dreux, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Unité de Neurobiologie et Pharmacologie Moléculaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Weill, Catherine, Unité de Recherche Clinique et d'Evaluation Scientifique URC28 ( URC28 ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Neurobiologie des processus adaptatifs ( NPA ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2005

48. Pharmacokinetic studies of scorpion venom before and after antivenom immunotherapy

Author: Krifi Mn, Sandrine Savin, Mohamed El Ayeb, Valérie Choumet, Cassian Bon, Marcel Debray, Institut Supérieur des Technologies Médicales de Tunis (ISTMT), Venins, Institut Pasteur [Paris], Laboratoire de Biomathématiques, Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This work was supported in part by the Réseau international des Instituts Pasteur et Instituts associés., The authors warmly thank Prof K. Dellagi (Head of the Institut Pasteur de Tunis) for his constant encouragements. They also address their thanks to Dr G. Rivière (Institut Pasteur de Paris) for its useful advice and fruitful suggestions. They are grateful to Drs Z. Ben Lasfar and K. Miled (Institut Pasteur de Tunis) for providing scorpion venoms, antivenoms and animals and their helpful discussions. They also express their gratitude to B. Saliou (Institut Pasteur de Paris) for his technical help., Institut Pasteur [Paris] (IP), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)
Subjects: Male, MESH: Antivenins/pharmacology, Time Factors, Androctonus australis, Injections, Subcutaneous, Antivenom, MESH: Rabbits, Scorpion Venoms, Venom, Biology, Toxicology, complex mixtures, Injections, Intramuscular, Neutralization, 03 medical and health sciences, Subcutaneous injection, Mice, Pharmacokinetics, Scorpion, MESH: Scorpion Venoms/immunology, Animals, Envenomation, MESH: Mice, 030304 developmental biology, 0303 health sciences, Antivenins, 030302 biochemistry & molecular biology, MESH: Time Factors, MESH: Injections, Subcutaneous, MESH: Scorpion Venoms/pharmacokinetics, biology.organism_classification, MESH: Injections, Intramuscular, MESH: Injections, Intravenous, MESH: Male, 3. Good health, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Immunology, Injections, Intravenous, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Immunotherapy, Rabbits, Intramuscular injection
Abstract: International audience; The improvement of the immunotherapeutic treatment of envenomations requires a better knowledge of the pharmacological actions of the scorpion venom and of the mechanism of its in vivo neutralization by antivenom. In the present work, we determined the toxicokinetic parameters of the toxic fraction of Androctonus australis garzonii venom in the absence and after antivenom immunotherapy, in experimentally envenomed rabbits. After subcutaneous injection of the scorpion venom, toxins showed a fast and complete resorption from the site of injection associated with a simultaneous distribution in a large extracellular compartment and with an important body clearance. The precocious intravenous injection of an appropriate antivenom dose was shown to induce an immediate, complete and durable neutralization of toxins, as well as their rapid redistribution from the peripheric compartment to the vascular one. On the contrary, the intramuscular injection of the same antivenom dose produced a slower and partial redistribution of toxins, leading to a delayed neutralization of the venom. The intravenous injection of smaller antivenom doses induced transient decreases of circulating toxins, indicating that a minimal antivenom dose has to be administered to allow an efficient and durable neutralization of the venom. We concluded also that this minimal effective dose of antivenom has to be injected precociously, by intravenous route, to achieve an efficient immunotherapy.
Published: 2004

49. GroEL (Hsp60) of Clostridium difficile is involved in cell adherence

Author: Marie-Claude Barc, Tuomo Karjalainen, Pierre Bourlioux, Fabrice Porcheray, Anne Collignon, Claire Hennequin, Anne-Judith Waligora-Dupriet, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Laboratoire St Marcel, Mairie de Paris, Université Paris-Sud - Paris 11 (UP11), Faculté de Pharmacie, CMES, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), and Université Clermont Auvergne (UCA)
Subjects: Operon, Immunoelectron microscopy, Molecular Sequence Data, Gene Dosage, Biology, Polymerase Chain Reaction, Microbiology, Bacterial Adhesion, 03 medical and health sciences, Heat shock protein, Chlorocebus aethiops, Animals, Humans, Amino Acid Sequence, Microscopy, Immunoelectron, Vero Cells, Enterocolitis, Pseudomembranous, 030304 developmental biology, GroEL Protein, 0303 health sciences, Base Sequence, Clostridioides difficile, 030306 microbiology, Chaperonin 60, Sequence Analysis, DNA, Fusion protein, GroEL, Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, enzymes and coenzymes (carbohydrates), biological sciences, bacteria, HSP60, Cell fractionation, Polymorphism, Restriction Fragment Length
Abstract: International audience; Previous results have demonstrated that adherence of Clostridium difficile to tissue culture cells is augmented by various stresses; this study focussed on whether the GroEL heat shock protein is implicated in this process. The 1940 bp groESL operon of C. difficile was isolated by PCR. The 1623 bp groEL gene is highly conserved between various C. difficile isolates as determined by RFLP-PCR and DNA sequencing, and the operon is present in one copy on the bacterial chromosome. The 58 kDa GroEL protein was expressed in Escherichia coli in fusion with glutathione S:-transferase and the fusion protein was purified from IPTG-induced bacterial lysates by affinity chromatography on glutathione-Sepharose. A polyclonal, monospecific antiserum was obtained for GroEL which established by immunoelectron microscopy, indirect immunofluorescence and immunoblot analysis that GroEL is released extracellularly after heat shock and can be surface associated. Cell fractionation experiments suggest that GroEL is predominantly cytoplasmic and membrane bound. GroEL-specific antibodies as well as the purified protein partially inhibited C. difficile cell attachment and expression of the protein was induced by cell contact, suggesting a role for GroEL in cell adherence.
Published: 2001

50. Identification and Characterization of Various Cholecystokinin B Receptor mRNA Forms in Rat Brain Tissue and Partial Determination of the Cholecystokinin B Receptor Gene Structure

Author: A. Jagerschmidt, Bernard P. Roques, T. Popovici, Michael J. O’Donohue, Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées (INSA), Unité de physicochimie et biotechnologie des polymères, Institut National de la Recherche Agronomique (INRA), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)
Subjects: Molecular Sequence Data, Hypothalamus, Gene Expression, In situ hybridization, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Biochemistry, Hippocampus, Polymerase Chain Reaction, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Receptor, Gene, In Situ Hybridization, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cholecystokinin, DNA Primers, Cerebral Cortex, 0303 health sciences, Messenger RNA, Base Sequence, Brain, Molecular biology, Receptor, Cholecystokinin B, Rats, Organ Specificity, RNA splicing, Cholecystokinin B receptor, Receptors, Cholecystokinin, Precursor mRNA, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery
Abstract: Using the powerful method of DNA amplification, we have been able to isolate several cholecystokinin B (CCKB) receptor (CCKB-R) mRNA forms from rat brain tissue, allowing the detection of a truncated mRNA species and the determination of the CCKB-R gene structure. Unspliced precursor mRNA and the mature form were identified in the cerebral cortex, hypothalamus, and hippocampus in apparently differing proportions according to the region examined, suggesting that the expression of the CCKB-R could be modulated at a posttranscriptional level. In the case of the cerebellum, only a completely unspliced mRNA form was detected, in agreement with previous studies in which CCKB ligand binding sites were not observed. In contrast, a truncated CCKB-R mRNA, lacking 250 bp, was detected in all the studied brain regions except for the cerebellum. This mRNA, for which a cellular function has not been assigned, potentially encodes a protein consisting of 168 amino acids.
Published: 1994

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